Kidney and Blood Pressure

                                                     Kidneys  and   Blood Pressure

                                                   PKGhatak, MD

A Blood Pressure (BP) of 120 mm Hg systolic and 80 mmHg diastolic, expressed as 120/80 mm Hg, is considered a normal BP in adults. When BP is over 140/80, it is called hypertension. In about 80% of cases, no definite cause of high BP will be detected. This is called Essential or Primary Hypertension. About 5 to 20 % of cases of high BP are due to kidney diseases.

Role of Kidney in maintaining a normal BP.

There are two systems that are operative. One is the Sympathetic nervous system and the other is the Angiotensin-Renin-Aldosterone system. These two systems are interconnected and act in a coordinated manner.

A. Sympathetic systems.

The BP sensors are located in the baroreceptors of the Carotid bodies and the Aortic bodies in the Aortic Arch. Any change in BP, high or low, initiates an impulse in the carotid stretch receptors in the carotid bodies and is carried by the Glossopharyngeal nerve and then relayed to the Hypothalamus. The pressure receptors of the aortic arch are sensitive only to falling BP. The Vagus nerve carries the sensation to the center and then relays it to the hypothalamus. From the hypothalamus, the outgoing impulse goes to the Celiac Ganglia. The postganglionic alpha fibers innervate all the systemic arteries and the beta fibers supply the heart.

The Hypothalamus also sends impulses to the adrenal glands and to the Juxtaglomerular cells of the kidneys.

Venous BP monitors: These are low-pressure monitors.

These monitors exist within large veins, pulmonary vessels, and within the walls of the right atrium and ventricle. Changes in volume influence the baroreceptors in the venous system and lead to the secretion of antidiuretic hormone and renin.

Effect of sympathetic alpha stimulation.

Arterial walls respond to alpha stimulation by increasing the tone of the muscular wall and the BP is raised. When the BP is high, the carotid body receptors produce a negative response in the hypothalamus, it prevents the further rise in BP. When BP falls, the aortic body sends positive impulses to the hypothalamus and BP is raised.

Effect of sympathetic Beta stimulation. Beta fibers mainly supply the heart. Stimulation of the beta fibers increases heart rate and force of ventricular contraction and elevation of BP.

Effect of sympathetic stimulation of the Adrenal glands. It increases the production and release of Aldosterone.

Effect of sympathetic stimulation of juxtaglomerular cells. It causes the secretion of Renin.

The action of the sympathetic system

Agent	Substrate	Response	Final effect
Alpha stimulation	Arterial wall	Vasoconstriction	BP elevation
Beta stimulation	Heart muscles	Rate and force of contraction	BP elevation
	Adrenal Glands	Aldosterone release	Increased Na+ absorption in exchange for K+
	Juxtaglomerular cells	Renin release	Angiotensin I formation
	Posterior Pituitary	ADH release	Blood volume increase

B. Angiotensin-Renin-Aldosterone system.

BP sensors.

The outer wall of the afferent arteriole of the kidney contains BP sensors. When blood flow/ pressure is low, these cells secrete Paracrine molecules (paracrine are chemicals, have actions like hormones but these chemicals are locally released and locally active). These molecules stimulate Juxtaglomerular cells to produce and release Renin.

Electrolyte sensors.

The Macula Densa cells of the distal convoluted tubules are specialized endothelial cells. They continuously monitor Sodium and Chloride concentrations of the glomerular fluid. Any fall in sodium chloride concentration triggers the paracrine release. Paracrine increases the rate of excretion of Potassium+ ion and H+ion production and release in exchange for Sodium+ ion from the filtrate.

Angiotensinogen is an alpha2 globulin produced by the liver and renal endothelial cells and circulates in the blood and is a non-active molecule. Renin converts angiotensinogen to angiotensin I. Angiotensin I is carried by the renal veins to the inferior vena cava to the right side of the heart and then to the lungs. In the pulmonary capillaries, the endothelial cells secrete Angiotensin Converting Enzyme (ACE). ACE converts angiotensin I to angiotensin II. In the blood, angiotensin lasts about 30 seconds and in the tissues for about 15 minutes, then it is degraded by ACE to Angiotensin III and Angiotensin IV. Both angiotensin III & IV have variable effects but are in the same line as angiotensin II.

Angiotensinogen is also produced by the fat cells, testicles, ovaries, brain, heart and blood vessels. In these secondary locations, its functions are limited at the local tissue levels.

Effect of Angiotensin II:

Angiotensin II has a multitude of functions. 1. It increases the tone of all systemic arteries and veins. 2. Constricts afferent and efferent arterioles of the glomerulus. and thereby increases filtration pressure and the GFR (glomerular filtration rate) is increased. 3. Angiotensin II increases the rate of Na+ ion reabsorption in the proximal tubules. 4. It accelerates Na+/K+ H+ exchange in distal convoluted tubules. 5. Angiotensin II causes the secretion of aldosterone by the adrenal cortex. 6. It releases an Antidiuretic hormone from the Posterior pituitary gland.

Na+/K+H+ ion exchange and water reabsorption produce an increase in total body Sodium and a decrease in potassium. The total body intravascular volume expansion takes place. The serum becomes alkalotic due to execs HCO3- ions. This condition is called Hypokalemia alkalosis.

Effect of Anti Diuretic Hormone (ADH).

ADH increases water absorption in the collecting tubules from the filtrate, thereby increasing blood volume. However, expansion of blood volume takes place only when both kidneys are ischemic. If only one kidney remains normal, then increased glomerular filtrate and loss of Sodium and water by the normal kidney in the urine keep the blood volume normal, but BP remains high.

Role of Kidneys in producing High BP:

Any condition producing a decrease in blood flow in the Kidneys (ischemic) produces high BP.

Renal causes of hypertension are discussed under

1. Renal- vascular

2. Renal parenchymal causes.

Of all the causes of Hypertension, renovascular hypertension has the most potential to be cured by corrective surgery and usually, the patients are not required to take BP medications. It is essential to find the cause of high BP before much damage takes place.

 1. Common causes of Renovascular hypertension.

In children:

Common causes are coarctation of the aorta, Moyamoya disease. Kawasaki disease, Takayasu arteritis, renal artery trauma, congenital renal artery hypoplasia or renal artery stenosis and renal graft stenosis following renal transplantation.

Moyamoya disease is more prevalent in Japan and is probably inherited by autosomal dominant inheritance. Cerebral arteries are deformed and various degrees of neurological symptoms develop at a very early age. Kawasaki disease is a multisystem inflammatory disease that usually follows a viral infection and produces signs and symptoms involving the skin, mucous membrane and lymph nodes and internal organs. It is more prevalent in China. Takayasu arteritis is an inflammatory disease of the aorta and its main branches,  producing narrowing of blood vessels and aneurysms,  producing severe ischemia to the involved areas like arms, neck, brain and kidneys. There is no known cause and treatment is not effective. It is often seen in Japan, Mexico, and India.

In adults:

The common pathology is renal artery stenosis due to atheromatous plaques.

The narrowing may be in one or both renal arteries. The plaques may be only segmental or in multiple areas, commonly involve the proximal third of the artery. The plaques develop the same way as in the coronary arteries. The risk factors are diabetes, high BP, high cholesterol, obesity, cigarette smoking, a sedentary lifestyle, and runs in a family.

Other causes of renal artery diseases are Congenital stenosis, Renal artery thrombosis, emboli, aortic dissection, A-V malformation, and aneurysm of the abdominal aorta.

In young females:

Fibromuscular dysplasia. This condition is largely confined to females of childbearing age. The condition may run in families. The medium size arteries are involved. Common sites are renal, intracranial, face and abdominal. The distal 2/3rd of the renal artery shows dysplasia. The changes may be confined in one or all three layers of the arterial wall. Bead-sized aneurysms are seen in cerebral branches of carotid arteries.

Risk factors are female hormones, the higher incidence of methysergide use in migraine, cigarette smoking, alpha 1 antitrypsin deficiency, cystic medial necrosis, neurofibromatosis, coarctation of the aorta and Ehler-Danlos syndrome.

The patients with fibromuscular hypoplasia are mostly symptoms free. A cerebrovascular episode like TIA, (transient ischemic attack) or subarachnoid hemorrhagic may lead to a diagnosis of fibromuscular dysplasia of the renal artery.

2. Renal parenchymal diseases cause hypertension.

Almost all inflammatory diseases of the kidneys raise BP.  A few common conditions are: -

Polycystic disease of the kidney. Glomerulonephritis.

Polycystic disease of the kidney is the most common hereditary kidney disease in adults causing hypertension and other complications. It is inherited as a dominant mode, and the expression of the defective gene penetration is variable. In children, the disease is much less aggressive and provides a better prognosis.

Glomerulonephritis is generally due to post-streptococcal pharyngitis, also seen in secondary to Bacterial endocarditis, Hepatitis B, hepatitis C, HIV infection and now COVID-19. Other less common causes are autoimmune glomerulonephritis. Lupus, Goodpasture syndrome, IgA nephropathy, Diabetic microvascular disease,

Investigation and Diagnosis:

The renal parenchymal disease is evident by the presence of protein, RBC, red cell casts and granular casts in the urine. If active infection is present, an increased number of WBCs and WBC casts are detected in urine. Further tests, including IgG, IgA and other serological tests are generally required for the determination of the etiology in individual cases. In most cases, needle biopsy of the kidney and special immunological staining is required to properly direct medical therapy and evaluate prognosis.

Renovascular disease is detected by an Ultrasonography of the abdomen. It is a noninvasive test and can easily detect abdominal aortic aneurysm, dissection of the aorta, atheromatous changes and fibromuscular dysplasia. The new generation Doppler ultrasound study gives flow and degree of stenosis. In case the presence of gas in the bowel interferes with the ultrasound study, MRI is an excellent alternative. The functional status of kidneys is determined by serum creatinine, urinary creatinine and GFR, electrolytes. Radio-opaque dye administration is held off till a definite surgery is planned. In a situation that is likely to be associated with vascular abnormalities of the brain and other vital organs, then a whole body angiogram may be completed before surgery.

Treatment:

Renal artery stenosis is treated by angioplasty and stent placement. This is the preferred treatment for fibromuscular dysplasia and a stent often is not needed.

Resection, repair and Dacron graft are used based on the nature of the pathology. In unilateral and atrophic kidney nephrectomy is indicated. Post-surgery prognosis is very good for children and young individuals.

******************************************

Kidney Stone

                                                                 Kidney Stone

                                                     PKGhatak, MD

Kidneys filter blood and eliminate harmful waste products from the body. The amount of work the kidneys perform is staggering. In a day, the kidneys filter 325 liters of the blood and produce 180 liters of glomerular filtrate. The reabsorption of most of the water, sodium, calcium and phosphate and the entire glucose load take place in the renal tubules. In the end, 1 to 1.5 liters of urine is produced in a day and the urine contains 1 to 2 meq of sodium out of 2,400 meq filtered, 100 % of sugar (about 162 gm), 95 % of calcium and 75 to 85 % of phosphates are reabsorbed. The waste products are urea, uric acids, creatinine, creatine, nitrate and sulfates. The amount of organic compounds in the urine of an adult on a regular western diet is as follows: urea 30 gm, creatinine 1.4 gm, ammonia 1 gm, uric acid 0.5 gm, protein less than 200 mg, and creatine 100 mg.

The worldwide incidence of kidney stones is increasing. Turkey reports that 14 % of its population experienced at least one attack of renal colic from real stone. In the USA the incidence is 11 % in males and 7 % in females. In the USA North Carolina has the highest reported kidney stones. The peak incidence of kidney stones is between 40 and 45 years of age. 

Mechanism of renal stone formation.

Two things have to happen for stone formation in the kidney. The supersaturation of any of these chemicals must take place - calcium, oxalate, uric acid and urea must take place. The second requirement is the presence of some foreign material or denuded cells in the glomerular filtrate around which the crystallization takes place and that grows into a stone.

Conditions favor stone formation.

Limited water intake, high sugar, and high salt intake are the important causes in otherwise healthy individuals. A diet containing an excess amount of calcium. phosphate, oxalate, protein and less citrate. Magnesium, uromodulin and pyrophosphate in the filtrate produce an imbalance promoting the precipitation of crystals. Obesity, excessive physical exertion in hot humid conditions, certain medications and heredity are also risk factors. Distal tubular acidosis, hereditary oxaluria and cystinosis are examples of autosomal recessive inheritance. Mendelian dominant inheritance is due to the mutation of 30 genes, but much work remains to be completed to define their importance.

Incidence of kidney stones

Type	Children %	Adult %	note
Calcium oxalate	50-60	60 - 80	Most common
CaPO4 Apatite	25	15	pH 6.8 to 7.4
hydroxyapatite		2	Very hard stone
Struvite	10	4	Infection and pH >7.8
Uric acid	3	10	Acid urine
Cystine	5	1
Other		2

Types of Renal Stones:

Kidney stones are classified as Calcium stones, Struvite stones, Uric acid stones, and Cystine stones. Calcium stones are calcium oxalate stones, calcium phosphates, Apatite and Struvite stones.

Formation of calcium oxalate stone.

In the basement membrane of the thin loop of Henle, calcium oxalate is deposited. It erodes through the basement membrane and accumulates in the subepithelial space renal papilla. This is known as Randell's plaque. Randell's plaque breaks down the cell layer and falls into the lumen. This provides the site for crystallization and stone formation.

Oxalate is present in leafy vegetables, rhubarb, root vegetables - potato, aram (taro), beets and almonds and cashew. Patients with Crohn's disease and colostomy develop fat malabsorption of fat leaving oxalate free in the small intestine for absorption resulting in high serum oxalate and kidney stones. In genetic disorders, primary oxaluria and cystinosis are characterized by repeated stone formation.

Calcium phosphate stone.

Apatite and Struvite.

Triple calcium stone is called Apatite. When one or more calcium molecules are replaced by Magnesium and rarely by iron molecules, the stone is called Struvite.

Calcium phosphate stones account for 15 % of all renal stones.

Calcium and phosphates are essential elements of the body and are present in every living cell. Metabolic processes generate serum calcium and phosphate in addition to food intake. Vitamin and calcium fortification of food also add to it. The current trend to take calcium and vitamin D supplements favors a further increase of these elements. High salt intake and diabetes are risk factors. If water intake lags behind then calcium reaches saturation points and calcium crystal forms.

Struvite stones.

Calcium phosphate stones in the renal pelvis occasionally become infected by the Proteus, Pseudomonas, Klebsiella group of bacteria. These bacteria generate ammonium from urea. Urea is the final product of amino acid metabolism. In alkaline urine, ammonia combines with urea. Ammonia urates stones grow rapidly in the pelvis of the kidney and the stone takes the shape of branched calyxes and these stones are known as Staghorn calculus. Patients with urinary retention require an indwelling catheter, infection by these bacteria produces calcium deposits around the catheter and multiple bladder stones.

Uric Acid Stone.

Purine and pyrimidine are nitrogen bases for the nucleotides which form nucleic acids. The end product of purine metabolism is uric acid in humans, in lower animals, the end product is Allantoin. High serum uric acid leads to gout and gouty arthritis. Uric acid is prone to form crystals in the urine when the pH of urine is acidic. Increased breakdown of the nucleus of cancer cells during the treatment of leukemia and lymphoma is a risk factor for uric acid stones.

Cystine stone.

Cystine stones are large stones and stones recur rapidly. This condition is inherited as an autosomal recessive mode. The patients have high blood amino acid cystine. It is filtered in the urine and forms stones. High sodium in the diet accelerates stone formation.

***********************************

Chronic Pancreatitis.

                                                     Chronic Pancreatitis

                                               PKGhatak, MD

Chronic pancreatitis is a devastating disease. Episodic severe unrelenting abdominal pain is the chief symptom. Progressive loss of weight and diarrhea of foul smelling stool are chronic symptoms. Alcoholism is the prime cause of this illness and cigarette smoking is an additive factor to alcoholism.

 Hereditary causes:

Hereditary predisposition to chronic pancreatitis is an important factor but the incidence of hereditary pancreatitis is low. The CFTR (cystic fibrosis transmembrane conductance regulator) gene mutation causes abnormal ductal secretion. CFTR is inherited as an autosomal recessive mode, and primarily affects bronchial glands producing thick sticky mucus but CFTR also affects the pancreas and other glands. SPINK 1 protein (serine protease inhibitor Kazal1) is a potent trypsin inhibitor. Mutation of the SPINK 1 protein gene prolongs the action of trypsin and damages the pancreas. Mutation of the PRSS I gene causes premature activation of Trypsinogen to Trypsin - a potent protein digestive enzyme of the pancreas. SPINK 1 gene is inherited as an autosomal dominant mode with 80 % penetration. Autodigestion of pancreatic tissue produces pancreatic insufficiency and the inflammation of the peritoneum causes pain. Progressive damage of Beta cells of the pancreas causes insulin deficiency and hyperglycemia.

Chronic pancreatitis, unlike pyelonephritis and bronchitis, is not due to an infection by viruses or bacteria. It is due to alcohol. A combination of pancreatic duct obstruction by stones or carcinoma of the head of the pancreas, sarcoma, lymphoma, etc. and alcohol abuse is the next important cause. About 40 % of chronic pancreatitis is due to alcohol, of the rest another 30 % are from a combination of pancreatic duct obstruction and alcohol, and in 10% no cause can be found.

How alcohol causes chronic pancreatitis.

Alcohol increases the protein content of the pancreatic secretion and decreases bicarbonate concentration resulting in the coagulation of protein. The coagulated protein globes block the pancreatic ducts. Alcohol increases the permeability of the cells lying in the ducts, and the pancreatic secretion spills into the pancreatic glands. Trypsin neutralizing enzyme production is decreased and trypsin action is prolonged. These result in chronic pancreatitis.

When this damage is repeated over 5 to 10 years, the damage to the pancreas becomes overwhelming and recovery becomes rare or impossible.

Other risk factors:

Increased incidence of chronic pancreatitis is seen in hypertriglyceridemia (usually 1000 mg +), hypercalcemia, abdominal surgery and trauma, and a Cardio-Pulmonary bypass procedure. ERCP (endoscopic retrograde cholangiopancreatography) and use of certain drugs. Rare incidences of autoimmune pancreatitis and systemic vasculitis are known.

Incidence:

About 50 in 100,000 people suffer from chronic pancreatitis and the rate has been going up since 1990. Men are more susceptible; the peak incidence is 40 to 45 years. The risk is proportional to the cumulative amount of alcohol consumed over the years.

Clinical Presentation. The First attack of pancreatitis.

The first incidence is acute pancreatitis. An attack starts after an episode of heavy drinking. Nausea and vomiting were soon followed by the onset of severe burning abdominal pain in the epigastrium and below the left ribcage. The pain is deep inside towards the back of the torso. At times the pain is felt on the left flank. The pain is so severe that the patient arrives at the ER immediately.

All the main signs of an acute abdomen are present on examination. The board like rigidity of the anterior abdominal wall indicates peritonitis. Depending on the severity and duration of the attack, cardiovascular compromise may be present.

Laboratory and imaging:

Indication of acute inflammation is evident by the presence of leukocytosis with a left shift, hemoconcentration, increased levels of liver enzymes, bilirubin, and alkaline phosphatase, which are indications of common bile duct obstruction. Proteinuria and the presence of sugar in the urine are usual findings. The severity of inflammation is judged by LDH over 350 units, AST over 250 units, CPK to 1000 + units, Creatinine over 1.8 mg, C-R protein to 1,500 mg/l. Low serum calcium of less than 8 mg indicates the binding of calcium with fatty acid produced by the digestion of body fat. A high Lactic acid, high LDH, high AST, and PaO2 less than 50 mmHg are bad prognostic signs.

Specific tests for acute pancreatitis are elevated serum Lipase and Amylase.  Amylase begins to rise in 3 hrs. and may reach 250 units and persist for 72 hrs., the Lipase increases in 50% of cases and may remain high for 14 days. High blood sugar is usually present.

Imaging: Ultrasound of the abdomen may not be the best test because the gas filled colon and small intestine interfere with image quality. MRI is more accurate and safer. MRI shows edematous pancreas and pancreatic duct dilatation. The dilated duct is due to obstruction of the duct by pancreatic stones or stones impacted at the sphincter of Oddi or a tumor of the head of the pancreas. Atelectasis of the lower lobes of the left lung and left sided pleural effusion may be present.

Clinical Presentation of Repeated attacks.

This first episode may not be the last in the majority of chronic pancreatic cases. Episodes of acute attacks, several times a year, are not uncommon. Repeated attacks damage the pancreatic exocrine (digestive) and endocrine (insulin production) functions to various degrees depending on the duration and frequency of acute attacks.

Acute abdominal pain may last several hours to 2 -3 days at a time. Marked weight loss and diarrhea of fatty stool are common symptoms. Signs of protein malnutrition are evident in the presence of hollowed out temples, sunken cheeks, skinny legs and arms.

Laboratory findings:

Laboratory findings in chronic pancreatitis are variable depending on the remaining functioning pancreatic tissue. Blood sugar levels are generally high, increased fecal fat points to malabsorption of fat and fat soluble vitamins A, D, E, and K.

Imaging;

MRI or CT of the abdomen is the initial test. 30% show various degrees of pancreatic calcification, and stones. The pancreas is generally atrophic and the pancreatic ducts are dilated. Secretin enhanced MRCP (a special MRI) to evaluate the hepatobiliary pancreatic system) maybe performed in difficult cases. Stones, stricture of the sphincter of Oddi and tumors are better detected by ERCP. Ultrasound study during ERCP increases visual evidence when cancer of the pancreas is suspected. Skinny needle biopsy done through ERCP scope provides a definitive diagnosis of malignancy. In chronic pancreatitis, the pancreatic tissues are in various degrees of degeneration, atrophic and replaced with fibrous tissue, the Beta cell islands are much reduced in numbers. The main pancreatic duct is dilated.

Management of Chronic pancreatitis:

The goals are pain control, prevention of future attacks, pancreatic enzyme replacement, and control of blood sugar by insulin. Pain control is crucial, success and failure depend on it.

Medical therapy:

The multidisciplinary team is better at managing pain and exocrine and endocrine deficiency brought on by chronic pancreatitis. Pancreatic enzyme replacement and insulin administration are effective in some patients but not universally. To control pain, non-opioid medications are tried to begin with but in the end, the majority of patients require opioids to control the intractable pain. Opioid addiction is a usual occurrence and becomes a major problem.

 Non-conventional treatments:

Mind-body therapy, acupuncture, chiropractic manipulation of the spine, touch therapy, dietary manipulation, supplements and antioxidant administration, etc. are tried and failed to show any improvement in pain and are disappointing.

Surgery for Pain control:

The sympathetic nerve fibers carry the pain sensation from the pancreas and the fibers originate from the T5 to the T12 segment of the spinal cord. The preganglionic fibers make a synaptic connection in the Celiac ganglion. The postganglionic fibers innervate the Pancreas, Liver- biliary system, vasculature of the small intestine and adrenal glands.

The head of the pancreas is considered the Pacemaker of Pain in chronic pancreatitis.

To assess the effect of sympathetic denervation, celiac ganglion block is performed. If effective then surgery is performed. The procedure is done by minimum invasive Laparoscopic method and is known as Bilateral thoracoscopic splanchnicectomy (BTS). The outcome of BTS is effective but the improvement may not last long. The main adverse effect of BTS is postural hypotension.

Drainage of Pancreas.

During ERCP, the dilated main pancreatic duct may be seen. If a stone is a cause, then the removal of the stone can be accomplished at the same time. If the stone is large or impacted, Extracorporeal Shockwave Lithotripsy is indicated. If dilatation of the sphincter of Oddi is performed, a stent is placed in the main pancreatic duct and drained for 6 to 8 weeks. In some cases, the drainage produces a significant decrease in pain. In those cases, an appropriate surgical procedure can result in a long term improvement.

Whipple Operation:

 In 1935 Whipple was the first surgeon to remove the head of the pancreas along with the duodenum. If the patients were able to abstain from alcohol and smoking for at least one year, they had significant relief from pain. However, the Whipple operation produced significant morbidity and mortality. Development of type 1 Diabetes mellitus, nutritional, iron, calcium and vitamin B12 deficiency followed the operation. The antrum and duodenum are not just conduits but both have exocrine and endocrine functions.

 The diagram above shows the Postoperative picture of a Whipple operation.

Modifications of the Whipple operation were undertaken by many groups in order to preserve as much duodenum as possible and save the tail of the pancreas and islets cells at the same time. To ensure adequate drainage of pancreatic secretion pancreatojejunostomy was performed.

Puestow modification 1958.

Puestow did not remove the head of the pancreas, instead opened the main pancreatic duct from the head to the tail followed by a side to side anastomosis of the main pancreatic duct and jejunum.

Berger modification of Puestow operation.

The above is a diagram of Berger's modification of the Puestow operation.

Burger modification preserved the duodenum and removed as much of the pancreatic head as possible by blunt dissection.

In 1960 Partington and Rochelle modified Puestow's operation by not including distal pancreatectomy.

Most recent modification.

In this operation, a total pancreatectomy followed by Islet cell autologous transplantation was performed to retain autonomous insulin production.

Various comparative studies were completed in order to find an operation that would control pain and produce minimum morbidity and mortality. Overall, all surgical procedures show some good control of pain but relapse in a year is common if patients go back to drinking and smoking.

Pain is the main reason the patient seeks medical attention for chronic pancreatitis. Medical and surgical treatment modalities are difficult to impose on patients because of significant morbidity. Patients with surgically correctable conditions like pancreatic stones, stricture of the sphincter of Oddi, and biliary obstruction have the best prognosis. Medically treatable conditions - hypertriglyceridemia and hypercalcemia also have a better prognosis. Overall pain control is achieved in 30-35 % of cases provided the patients abstained from drinking alcohol and stopped smoking. Opioid addiction is very difficult to avoid because of constant and unrelenting pain, and when other methods are ineffective. About 4 % of patients with chronic pancreatitis develop cancer of the pancreas but in the hereditary condition, the cancer rate increases to 20%. Increased incidence of venous thromboembolism, increased risk of CAD and other acute vascular events are known because of changes in coagulation factors and platelet function.

Written in memoriam of Sanjay Banerjee. 1965 - 2012.

************************************************

Genes Controlling Human Hair Color.

                                        Genes controlling human hair color

                                             PKGhatak, MD

The hair colors of humans are black, brown, blond, grey/white and red. And then there are many shades in each of the colors and in-between colors. It is not usual to see children born to the same couple have different hair colors. This is the magic of genes in the chromosomes.

The MC1R gene is the primary gene for human hair color. The gene MC1R is carried by chromosome 16 on the long arm q at 24.3 location (16q24.3). The deeper layer of the skin contains melanin forming cells, melanocytes. MC1R gene in a dominant and active stage produces a good amount of black pigment melanin known as Eumelanin. In MC1R mutation and in the inactive stage, produces a yellow-red pigment called Pheomelanin.

In lower mammals, another gene ASIP (agouti suppressor protein) contributes red color. In humans ASIP gene is absent but its role is exhibited in the inactive MC1R gene. Genome wide association study (GWAS) discovered Single Nucleotide Polymorphism (SNP) and its effects on the genes. The SNP in a particular locus modifies the function of the gene in an individual. About 200 SNPs are identified in the European population with blonde to light brown hair color.

In Mendelian inheritance, an individual is either in dominant or recessive mode. In dominant inheritance, there are variations of expression of gene function due to co-dominance. In addition, multiple genes may influence the same characteristic. Varieties of gene interactions are the reasons for so many shades of hair colors and the same parents having different hair colors for their babies.

Hair:

Hair has two parts, the root and the shaft. The root of the hair lies deep in the basal layer of the epidermis of the skin. The root of hairs is supplied with branches of blood vessels and nerve fibers. This is the living part of the hair.

The shaft that lies above the skin is dead tissue. The center of the shaft is called the medulla and it is surrounded by several layers of densely packed cells forming the cortex. In the cortex, the keratinocytes containing the melamine pigment lie. The outer layer is the cuticle, made up of a single layer of cells containing a protein called keratin. Several genes express the texture, length, waves, curls and luster of hair. All these genes, including the MC1R gene, are responsible for the way hair looks.

Melanin.

The melanocytes produce melanin from the amino acid tyrosine. Tyrosine is converted in stages to DOPA then to L-dopaquinone then to eumelanin or phaeomelanin pigment. The long arm of the melanocyte deposits the pigment in the keratinocytes in rows like a string of pearls.

Chemically, 5 types of melanin are present, but eumelanin and pheomelanin, the two organic melanins, are present in human skin, hair, eyes, and adrenal glands. The third one, Neurological, is present in the substantia naira of the midbrain, the decreased melamine production is responsible for Parkinson's disease.

Grey / White hair.

As hair grows at the hair root the hair is colorless, and the pigment cells melanocytes surround it. In old age, and in certain diseases and genetic conditions, melanin stops forming. The new hair that emerges looks grey or white. Australia has the most grey haired people in the world due to the effects of bright sunlight on their heads.

Red hair.

Red hair is the least prevalent when the entire world population is considered. Red hair is principally seen in Irish and Scandinavian people and their descendants in other countries.

Blond and different shades of brown hair.

The European population and their descendants carry these genes. As discussed before, multiple genes including NSP polymorphism are responsible for varieties of shades.

Black hair.

African, South Asian, and Chinese people have black hair. Chinese people by a long tradition used to headcovers and they retain black hair color longer in old age than any other race. It is said that stress can change hair to white or grey overnight. That is an exaggeration, however, stress and stress hormones depress melanin formation.

***********************

Red Eye

                                                                    Red Eye

                                                     PKGhatak, MD

Eyes develop from the forebrain as an extension of the central nervous system but mystics believe eyes are portals to the soul. Some others claim they can judge a man whether is innocent or guilty by looking into his eyes. Poets, writers and musicians love to associate eyes with all the beautiful things in this universe. Eyes are really remarkable by any measure.

But the physicians see the eyes as specialized organs but like other organs, they are subject to infection and diseases.

The tiny blood vessels on the surface of the layer of the eye are colorless and the underlying layer is called the sclera, which is the white of the eye. In the center of the sclera is a transparent cornea through which light passes without distortion to the retina where the process of vision begins.

Eyes turn red due to congestion of conjunctival blood vessels or actual rupture of blood vessels. The oxygen of air binds with hemoglobin, separated by the thin layer, and so bleeding or congestion of the conjunctiva looks so red. Some call it bloodshot eyes, commonly seen in deprived students before examinations, or those who had too much to drink at a fraternity party.

Red eyes are common in conjunctivitis, keratitis (inflammation of the cornea), corneal scratches, foreign bodies in the eyes, glaucoma, subconjunctival hemorrhage, chemical burns, and certain systemic diseases.

Conjunctivitis is of three categories: acute, chronic, and a part of systemic diseases.

Acute conjunctivitis: conjunctivitis can develop acutely from viral or bacterial, parasitic infections, or from chemical irritation like tear gas or pepper spray. Allergic red eyes are a common occurrence in spring and fall. There are many other causes of red eye.

Viruses.

Many viruses can produce conjunctivitis and common among them are Enterovirus, coxsackie, adenovirus, herpes virus, rubella and measles viruses. Rare but locally endemic viruses like Dengue, Hantavirus and Ebola can produce conjunctivitis. Ophthalmic herpes zoster is a serious disease that requires careful medical management.

Adenovirus 8,19, and 37 produce a severe type of acute painful conjunctivitis known as Keratoconjunctivitis. Enterovirus 70 and coxsackievirus A24 produce hemorrhagic conjunctivitis in tropical and subtropical countries. Herpes simplex can cause blisters on the conjunctiva.

Bacterial conjunctivitis.

In adults, a severe form of infection is seen in Neisseria gonorrhea and N. meningitidis infection. Purulent discharges are loaded with bacteria and very contagious. The infection of the eyes spread very rapidly. Before the days of prenatal care, gonococcus eye infection in newborns took place during birth and was a major cause of infant blindness. Children are susceptible to H. influenzae, Streptococcus pneumonia, Staphylococcus and Moraxella conjunctivae.

Chlamydia trachomatis produces recurrent conjunctivitis, scarring of the inner aspect of eyelids and cornea. It is common in the poorest parts of the world. It is an important cause of blindness and it is preventable by the timely administration of antibiotics. Reiter's syndrome is also produced by Chlamydia in young adults. This is a combination of arthritis, conjunctivitis and urethritis.

Chronic Conjunctivitis.

When conjunctivitis persists over 4 weeks, it becomes chronic in nature and the eyelids are infected producing redness along the eyelashes and shedding of flake derbies and swelling of the eyelash margin. Common bacteria causing the chronic infection are Streptococcus and Moraxella.

Allergic conjunctivitis.

Besides pollen, other common causes of allergic conjunctivitis are mascara, contact lens and lens solution, animal dander, molds, mites and cigarette smoke.

Vernal keratoconjunctivitis is an IgE mediated allergic, self limited but recurrent episodes of inflammation of the cornea and conjunctiva.

Dry eyes.

It is commonly seen in the elderly from decreased tear formation. In others chronic inflammation due to autoimmune disease, Sjogren's syndrome, scleroderma, psoriasis and use of cholinergic drugs. The dryness of conjunctiva produces a gritty sensation and burning sensation and produces redness of the eyes.

Subconjunctival hemorrhage. 

It is common in the elderly, particularly those taking Aspirin and blood thinners. Vigorous rubbing of eyes, staining like cough or sneezing ruptures blood vessels of the conjunctiva. Usually, one eye is affected. The patient may be alarmed but it is a benign condition and the blood disappears in a few days.

Transitional causes of red eyes.

Crying spell. hot showers, emotional upset, trauma, eye drops, dust or eyelashes in the eye, frequent touching of eyes.

Parasitic conjunctivitis.

Loiasis.

Loa loa is a nematode, a parasitic worm. Larvae of loa loa enter the human flesh through bites of a female deer fly and mango fly, called Chrysops demidita and C. silacia. The mature worms migrate through the body and at times pass underneath the conjunctiva and produce severe conjunctivitis. WHO estimates about 10 million people suffer from Loiasis.

Acanthamoeba.

It is a protozoan present in soil and tap water. If tap water is used to clean contact lenses then the infection may occur.

Damodex folliculorum. 

It is a mite, lives under the eyelashes and eyebrows. Infestation produces itching, red eyes and shedding of dry skin. It usually becomes chronic.

Toxoplasmosis.

Toxoplasma gondii is a facultative intracellular parasite, infection is usually acquired congenitally and immunosuppressed people can get infected from cat litter. The infection is mainly located in the retina but may also infect the cornea and conjunctiva.

Myiasis.

 A fly that usually feeds on Caribou called Botfly, can bite humans and lay eggs in the wound. Hatched eggs, maggots, feed on living human tissues. Maggots develop into adult worms and migrate throughout the body.  In the eyes, adult worms cause severe conjunctival inflammation, glaucoma and detached retina.  

Systemic diseases.

The following diseases are often associated with eye involvement and the red eye is just a part of them.

 Systemic Lupus Erythematosus, Rheumatoid Arthritis, Scleroderma. Temporal Arteritis, Periarterites Nodosa, Sarcoidosis, Migraine,

Venous obstruction. Central retinal vein occlusion, Superior vena cava obstruction, constrictive pericarditis.

Graves' disease of the thyroid gland. Hyper-viscosity syndrome from multiple myeloma. Sickle cell disease. Serum sickness, Steven-Johnson syndrome, etc.

Glaucoma. Glaucoma is usually seen in the elderly but no group is immune from acquiring it, even a rare congenital form exists. In glaucoma, the hydrostatic pressure of the eyeball exceeds venous pressure resulting in damage of the retinal structure mainly in and around the Macula, a special area of acuity and color vision of the retina. This is a major cause of vision problems and blindness. Glaucoma is effectively treated before much damage has taken place.

*************************

Trace Elements and Human Health

 

                                        Trace Elements and Human Health

                                           PKGhatak, MD

The elements making a human body are of three categories. Elements that are plentiful like carbon, oxygen, nitrogen, hydrogen, etc. These elements form covalent bonds and make up the tissue; the less plentiful elements are sodium. chloride, potassium, etc., which are responsible for maintaining osmotic pressure gradient between cellular and extracellular fluid and finally elements that are rare like zinc, copper, chromium, cobalt, selenium, magnesium, and molybdenum. These trace elements are bio-active substances or parts of many enzymes system responsible for various functions of the body.

In addition, elements found in human tissues are not parts of normal tissue or serve any useful purpose but accumulate in the body due to persistent exposure and often are harmful to the body, for example - lead, arsenic, mercury, etc.

Trace elements and their functions.

The trace elements have similar dietary sources, digestion, absorption and transport systems. The elements differ mainly by the enzyme they form, even then many enzyme systems containing the trace elements participate in a sequence on the same substrate or metabolic process. This is particularly true with copper, zinc and manganese.

There are more than one standard daily requirement numbers - usual daily intake, recommended daily allowance, no adverse effects on a minimum dose, adverse effects on a dose and then various ratios. This also added confusion about the amount safe to take and should be good for the body.

Selenium.

Selenoproteins and selenium containing proteins are required for DNA synthesis, also needed for thyroid hormone production and metabolism. Selenium provides protection against infection.

Selenium exists in two forms: inorganic and organic forms. Most selenium in human tissues is incorporated non-specifically with the amino acid methionine. Skeletal muscle is the major site of selenium storage. Both selenocysteine and selenite are reduced to generate hydrogen selenide, which in turn is converted to selenophosphate for selenoprotein biosynthesis. Selenium is active as an anticancer agent; it prevents ischemic heart disease and selenium has vitamin E like effects on the body.

Daily requirement. 55 to 70 micrograms. Selenium containing food are Brazilian nuts, seafood, animal organs, cereals, shellfish and dairy products.

Chromium.

Chromium in nature exists as trivalent and hexavalent forms. Chromium is a part of the glucose transport protein. For organic processes, trivalent form is required and chromium is present in the enzyme system involved in the catabolism of fatty acids and carbohydrates. It is also required for the synthesis of cholesterol. It is also considered an antioxidant. Excess chromium is considered a risk factor for carcinoma of the lung, and premature atherosclerosis. Chromium poisoning produces GI upset, peptic ulcers, liver and kidney dysfunction and growth retardation in children. It is required for parenteral nutrition. The daily dietary requirement is 35 micrograms for adults.

Manganese.

It is one of the trace element constituents of superoxide dismutase, required for mitochondrial functions and integrity of the cell membrane. It is needed for carbohydrate, cholesterol and protein metabolism, sex hormone production and growth in children. Like many other trace elements, it is required for brain cell development, connective tissue, bones & joints and blood clotting.

Manganese is absorbed in the small intestine through an active transport system and, possibly by diffusion when oral intakes are high. After absorption, some manganese remains free, but most are bound to transferrin, albumin, and plasma protein alpha-2-macroglobulin. Manganese is taken up by the liver and other tissues. The daily requirement is 2 to 2.5 mg for adult males, women need lesser amounts. In poisoning from excess exposure in welding, the alloy industries and agriculture. Excess manganese in the body may produce neurological symptoms including Parkinson's disease. In iron deficiency anemia and liver cirrhosis, the adverse effects of Manganese develop more readily.  Leafy green vegetables, green tea, and whole grains are good dietary sources of chromium.

Molybdenum.

Molybdenum is required for processing DNA and other proteins. Molybdenum is a structural constituent of a cofactor and is required for the function of four enzymes- sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reducing component (mARC). These enzymes metabolize sulfur-containing amino acids and heterocyclic compounds including purines and pyrimidines. Xanthine oxidase, aldehyde oxidase, and mARC are involved in metabolizing drugs and toxins.

The kidneys are responsible for Molybdenum excretion. Molybdenum, in the form of molybdopterin, is stored in the liver, kidney, adrenal glands, and bones. Molybdenum deficiency is rare.

Serum levels of molybdenum range from 0.28 ng/mL to 1.17 ng/mL. Daily requirement – 45 to 50 micrograms.
Legumes are the richest sources of molybdenum. Other foods high in molybdenum include whole grains, nuts, and beef liver.

Cobalt.

Cobalt lies in the center of the vitamin B12 molecule. The role of B12 in humans is well known and discussed in an earlier blog (see vitamin B12 blog). Besides its role in RBC, cobalt is required for nerve cell formation, as a neurotransmitter, and for nerve impulse conduction. Food is the main source of cobalt but it can be absorbed through the skin from prolonged contact and by inhalation of contaminated air. Surgical implants containing cobalt can leach and can produce toxicity, produce chronic inflammation from increased production of IL-1 and IL-6 and TNF-alpha from the macrophages.

Toxicity to cobalt results from depression of cellular respiration because of the downregulation of the cytochrome P-450 enzyme. Other enzymes like catalase and aminolaevulinic synthetase involved in tissue respiration are also depressed by cobalt toxicity. Depresses Kreb cycle enzymes decrease energy and metabolism. Cobalt can replace zinc in enzymes like alcohol dehydrogenase and can increase alcohol toxicity. In toxic levels, cobalt interferes with Iodine and may result in thyroid goiter.

Copper.

Enzymes containing copper cuperoenzymes have various functions in the body.  Cuperoenzymes are needed in brain development, immune functions, angiogenesis, skin pigment production. Iron absorption and incorporation of iron into RBC is copper dependent. Copper is an important oxidase enzyme system. Ceruloplasmin, hephaestin and zyklopen are important among them. The iron transport protein - Ferroprotein, depends on these enzymes for a steady supply. Cytochrome C oxidase, required for so many cellular functions, is a copper-containing enzyme system. Copper, zinc superoxide dismutase (CuZnSOD), is an antioxidant enzyme. K562 cells, a human erythroleukemic cell line, can extract copper from ceruloplasmin and incorporate it into CuZnSOD.

Only a small amount of copper is present in the body, and is mainly present in the skeleton and skeletal muscles. The daily requirement of copper for adults is about 900 micrograms. The main dietary sources of copper are seafood, animal organs, nuts, beans and chocolate. A small amount of copper enters food during cooking in copper wares and vinegar, wine added during cooking accelerates copper leaching into food and may cause poisoning. Excess flux used in copper plumbing in the previous generation is another source of copper poisoning. Acute copper poisoning and suicide attempts using copper sulfate are common occurrences. Excess copper is harmful to the body. Copper produces liver disease - acute hepatitis and liver necrosis after ingestion of a large amount. Chronic copper poisoning is seen in an inherited autosomal recessive disease - Wilson disease, from accumulated copper in the liver producing liver cirrhosis, copper deposits on the cornea and other tissues containing ceruloplasmin. An X-linked recessive inherited disease - Menkes disease, (a similar inherited defect like Hemophilia A), is due to the ATP7A gene. Mutated genes produce defects in copper transport, leaving excess copper in the small intestine and renal tubules and at the same time, a deficiency of copper in hair, skeleton, blood vessels, structural abnormalities and nerve cells suffer from deficiency. 

Zinc. 

Zinc is involved in numerous aspects of cellular metabolism. Zinc is part of approximately 100 enzymes and it plays a role in immune function, protein synthesis, wound healing, DNA synthesis, and cell division, lymphocyte proliferation response to mitogen, Immune defects produce abnormal binding of nuclear factor kb and decrease in DNA, decreased production IL-2(interleukin 2) and killer T-Cells. Zn acts as an antioxidant. Zinc deficiency can impair macrophage and neutrophil functions, natural killer cell activity, and complement activity, and normal growth and development. Zinc is required for a proper sense of taste. Humans have no specialized zinc storage system.

The daily requirement of zinc is 9 to 12 mg, excess intake can interfere with copper absorption and anemia.

Zinc deficiency is usually common in India, mostly in breast milk-fed children.  Frequent infections, diarrhea and growth retardation and hypogonadism are presenting symptoms. Excess Zinc in the elderly is not a rare occurrence in these days of megavitamins and heavy doses of mineral intake. It appears that many elders believe - " if 1 microgram is good then 1 gm will be better." Excess Zinc interferes with iron and copper abortion and incorporation of iron in the RBC, and copper-containing enzymes.  Zinc substitution of other trace elements in enzymes results in a poor functioning immune system, and frequent infection.

The gene SLC39A4 defect, either acquired or inherited as autosomal recessive mode, results in a lack of absorption of zinc from the small intestine. The disease is characterized by pustular dermatitis around the mouth and anus, diarrhea, nail dystrophy, and poor health. This condition is known as Acrodermatitis enteropathica.

The buzzword of this generation is Anti Oxidant. Nutritional supplements and various chemicals marketed as antioxidants are sought after substances. It is better to be prudent and a bit skeptical before ingesting chemicals that could poison the brain, liver and kidneys.

****************************

 

Penicillin Allergy

                                                               Penicillin Allergy

                                                        PKGhatak, MD

Penicillin was the first antibiotic that came into the medical field and it proved far superior to sulfonamides. On the battlefields, Penicillin was the only antibiotic available for the treatment of wound infections.

Soon, Penicillin was prescribed on a wider scale for the public. Reports of allergic reactions and anaphylaxis began to surface, making doctors take a careful history of penicillin allergy before prescribing penicillin.

10 % of patients reported being allergic to penicillin G, penicillin related compounds, and cephalosporins. At present, true penicillin allergy is seen in 3 % of users, and the rest of the reactions are nonallergic minor symptoms.

Molecular basis of Penicillin allergy.

Penicillin is a Dipeptide. The structure of penicillin consists of a beta-lactam ring, a thiazolidine ring, and a side chain of 6 amino acids. The allergenic property of penicillin lies within the β-lactam ring. Penicillin is a Hepten. It binds readily with plasma protein and becomes antigenic in susceptible individuals.

Why do certain people develop a Penicillin allergy:

The adaptive immune system produces IgM (Ig = immunoglobulin) and IgG classes of antibodies; IgA class antibodies in the GI, Respiratory, and Genitourinary tracts. IgE( immunoglobulin E) antibody is produced in the regional lymph nodes draining the location where the offending organism entered the body. However, the antigen must have these characteristics:

1. The antigen must be a small molecule of protein; if the antigen is not a protein, then it must be a Hapten. A hapten binds readily with a protein and becomes an antigen.

2. The antigen must be soluble so that the Dendritic cells can recognize it as a foreign substance.

3. The molecule of antigen has to be small. 

The plasma cells, in the lymph node genome center, switch IgE antibody production under the influence of CD4 and Th2 (thymic 2) cells. A low dose exposure of Penicillin on the Th2 cells produces Interleukin IL-4 and IL-13. Those two Interleukins are the molecular switch for IgM and IgG production. If penicillin exposure is large, then Th1 cells are activated. Th1 cells produce IFN gamma (interferon-gamma), IFN gamma acts as a brake on Th2 cells, and Th2 cells stop producing IgM and IgG antibodies.

Penicillin-induced Hypersensitivities are in two categories. 1. Immediate,

 2. Delayed.

 The reactions are also referred to as Type I to 4 Hypersensitive Reactions.

Immediate Reaction.

Type I. - Immunoglobulin E-mediated immediate reaction, occurs minutes to hours after exposure to the antigen.

Delayed Reaction.

Type II. -  Immunoglobulins IgM and IgG mediated Cytotoxic reaction, occurs 72 hours after exposure.

Type III. - Immune Complex reaction occurs 10 to 12 days after exposure.

Type IV. - Cell-mediated Delayed reaction occurs 4  days after exposure.

Special features of IgE.

IgE differs from other Ig classes of antibody in being locally produced and most abundant in local tissue. IgE has a high affinity for the skin resident Mast cells, FCεRI receptors. IgE also binds to some degree to eosinophils and basophils. Repeat exposure to the antigen releases pre-formed Bradykinins, Histamine, and other enzymes locally. That produces allergic symptoms. In Anaphylaxis, the mast cells, eosinophils, and basophils all empty preformed enzymes simultaneously, producing swelling of the mucosa of the tongue, pharynx, upper airway, obstruction, hypotension, hypoxemia, and cardiovascular collapse.

Detecting IgE in Allergy and Anaphylaxis.

The tests are in two groups, namely, Skin Tests and Blood Tests. The skin tests are the Scratch test, Intradermal test, and Patch test. The first two tests are for detecting IgE antibody against Penicillin, and the Patch test is for detecting delayed skin reaction to Penicillin. The scratch test is performed on the forearm. A drop of a standard solution of penicilloyl-polylysine or undegraded penicillin is applied to the skin. A fine needle is used to lightly scratch the skin through the liquid. In 15 to 20 minutes, a wheal should appear if the person is allergic to penicillin. The wheal is measured with a ruler. The degree of sensitivity is proportional to the diameter of the wheal.

The specificity and sensitivity of the scratch test can be improved by injecting the same penicillin solution between the layers of the skin. And the resultant wheal is measured the same way the scratch test is done.

The patch test is described later under delayed hypersensitivity reaction.

A skin test is generally considered a standard test for allergies. This test, however, has considerable risk. It may precipitate a severe allergic reaction or anaphylaxis.

That risk is totally eliminated by performing a blood test. A modified RAST       (radio-allergo-sorbent test) blood test - CAP RAST or  CAP FEIA (fluorescence enzyme immune test). Blood is collected from the patient. At the laboratory, tiny discs coated with penicillin are mixed with serum. After a certain time, when the IgE antibodies bind with the antigen is complete and the unbound IgE is washed away. The bound IgE is quantified by fluorescent enzyme immunoassay.

The blood test has a significant false positive result, but a negative result is confirmation of the absence of penicillin allergy.

Type II Penicillin Hypersensitivity.

Penicillin molecule at times binds with the normal cells' surface receptors. This new molecule is perceived by the immune cells as foreign. Antibodies of class IgM and IgG are generated. The antibodies attack the penicillin-bound normal tissue or the extracellular matrix. This triggers the activation of complement, producing matrix destruction and loss of function. Examples of type II hypersensitivity are acquired hemolytic anemia, Thrombocytopenia, and Leukopenia.

Type III penicillin Hypersensitivity.

In type III hypersensitivity, the IgG antibody is combined with penicillin. These antigen-antibody complexes are deposited in tissues. The immune cells are activated against this complex. The immune inflammatory reaction causes tissue damage and loss of function. Examples are Serum sickness (fever, arthralgia, urticaria, lymphadenopathy, and glomerulonephritis), Vasculitis (multiple organ involvement – hepatitis, nephritis, pneumonitis, skin lesions, etc.). Interstitial nephritis.

Type IV penicillin Hypersensitivity.

Penicillin ointments, creams, and drops were used to treat wounds. Penicillin sensitized the skin's immune cells. Sensitized immune cells produce inflammation in the skin area and the condition is called contact dermatitis. This preexposure to penicillin produced penicillin resistant bacteria. Now, this practice is abandoned, and contact dermatitis due to penicillin has greatly disappeared. Examples of delayed reactions are - Contact dermatitis, morbilliform skin eruptions, Stevens-Johnson Syndrome (SJS), and a more severe form of SJS, Toxic Epidermal Necrosis (TEN).

Footnote:

Skin test for Type IV reaction. A small piece of sterile dressing soaked with penicillin solution is applied to the back of the patient and kept in place by an occlusive dressing for 4 days. When the dressing is removed and the presence of skin lesions is noted.

Stevens-Johnson Syndrome: Flue like symptoms, rapidly spreading skin lesions which quickly turn into blisters. Mouth, lips, and throat swell and become painful and bleed easily, and becomes fatigued. Shedding of layers of skin and rapid deterioration of the condition, an emergency situation develops.

edited June 2025.

*************************************

Insulin Resistance.

                                                    Insulin Resistance

                                               PKGhatak, MD

Insulin is an essential hormone for glucose utilization. In the absence of Insulin, blood sugar is elevated and the body is unable to generate an adequate amount of energy and many other metabolic processes are derailed. Unless Insulin is administered, death is inevitable. This is called Type I Diabetes mellitus (DM1). Type I diabetes is not a part of today's insulin resistance discussion.

In Type II Diabetes mellitus (DM2) the Insulin is either structurally abnormal or due to the presence of circulating antibodies making Insulin less effective. In this condition, the blood sugar is high and Insulin levels are high to high normal. A recent study from Japan showed DM2 might result from an increased renal insulin clearance and high sugar is due to relative insulin deficiency. WHO reported that    Covid-19 can destroy beta cells of the pancreas as documented in long covid.

An outline of Insulin activities.

Chemically Insulin is a polypeptide. Polypeptide hormones are prone to structural abnormalities due to minor defects in the cleavage of the long chain amino acids, which make the polypeptides. Some other non-insulin polypeptides have Insulin-like actions. Notable among them are Insulin-like growth factor I and II (IGF1 and IGF2).

Insulin Carrier Proteins:

Insulin molecules are transported by carrier proteins to cells. The cell surface contains receptors for Insulin. Insulin receptors are made up of two units - an A unit and a B unit. The distribution of A and B units is not uniform in the tissues. The binding of insulin with a specific receptor A or B determines the metabolic path the glucose molecule takes inside the cell. Moreover, when Insulin binds with one unit, then the other unit becomes inactive. In the Liver, however, Insulin binds with both units A and B. As a result, Insulin in the liver makes multiple metabolic paths unlike in other tissues. Insulin, on binding with the cell receptors, facilitates Glucose entry inside the cell and also stimulates the hexokinase pathway for the utilization of glucose and ATP generation.

Transport of Glucose molecules in and out of cells:

The glucose transport proteins belong to two groups. One is energy-independent Glucose transport proteins (GTP 1 to 13) and the second one is Sodium-Glucose Linked Transporters (SGLTs) and this requires energy expenditure.

GTP 1. This transporter helps a low-level glucose entry into all cells for tissue respiration.

GTP 2. This transporter is bidirectional. In the intestine, renal tubules and beta cells of the pancreas GTP 2 ferries glucose in and out of cells under the concentration gradient.

GTP 3. This transporter is most active in the nerve cells of the brain and spinal cord.

GTP 4. It is most prevalent in cardiac and skeletal muscles.

Energy dependent SGLT.

Energy is used for Sodium, Potassium, and H ion exchanges to maintain Intracellular pH and blood/cytosol Na and K concentration gradients.

During this process, Glucose enters the cell when a relative Na+ ion (sodium ion) deficiency develops. In high plasma glucose concentration, the process is reversed. In post digestion, glucose absorption in the small intestine and renal tubular conservation of filtered glucose are examples of SGLT1 transport.

Besides these sites, three other sites - Liver, Muscles and White Fat Cells (WFC) are the main focus of Insulin resistance and require attention.

Liver: The liver is the prime metabolic workshop. 1. Glucose is metabolized via tricarboxylic acid cycle, 2. Excess glucose is converted to glycogen, 3. Glucose is generated from fatty acids and amino acids and 4. Glycogen is broken down to glucose. All these metabolic processes are enzyme driven and take place in cellular mitochondria and endoplasmic reticulum (EPR).

Muscles: 1. Glucose is utilized in the muscles as fuel, 2. Excess glucose is stored as glycogen, and 3. glucose is generated from glycogen.

White fat cells (adipocytes): 1. Fatty acids are stored as fat molecules. 2. And fat provides energy when needed by turning back into fatty acids and glycerol.

Just as these organs differ the way glucose is utilized, similarly when Insulin resistance develops, these organs are affected in different ways and the degree of effects are variable.

Clinical entities associated with Insulin resistance.

1. Metabolic syndrome. This entry consists of hypertension, fatty liver, hyperlipidemia, high blood sugar and abdominal obesity.

2. Polycystic ovary syndrome.

3. Pre-diabetic stage.

4. Lipodystrophy.

5. Non-alcoholic fatty liver disease.

Mechanism of intracellular Insulin resistance in Type II Diabetes mellitus.

1. Structural abnormality of Insulin.

2. Presence of circulating Insulin antibodies.

3. Inherited mutation of genes expressing Glucose transport proteins and glucose receptors of cells.

4. Acquired mutation of genes expressing glucose transport proteins and glucose receptors. 

5. Stress and Inflammation.

Stress.

Stress. Excess accumulation of lipids inside the cells diverts the metabolic path from the tricarboxylic cycle to the utilization of fat. This puts an extra burden on mitochondria and the endoplasmic reticulum.

Inflammation

Inflammation. Inside the cell cytoplasm, various inflammatory cytokines like IL-6, IL-10, and TNF-alpha1 accumulate. Obesity is now considered as a chronic inflammatory condition of fatty tissue.

 6. Molecules of intermediate products of metabolism like bioactive lipids, diacetyl- ceramide, acyl carnitine produce mitochondrial stress and inflammatory cytokines. 

7. Glucagon or ACTH, glucocorticoids secreting tumors

8.  Endocrine abnormality. - Hyperthyroidism, Gigantism and Acromegaly. Cushing disease.

9. Growth hormone of the anterior pituitary is antagonistic to Insulin in the skeletal muscles and liver.

10. Medication. - A common cause of high blood sugar is chronic use of systemic steroids used in immunosuppression following organ transplants and asthma and certain hematological malignancies. Other drugs may elevate sugar are Hydrochlorothiazide, Statins, Beta blockers, Amiodarone, Niacin, Antipsychotic drugs and Prostaglandin E1.

************************************