Additional information

Common causes of esophagitis

Drugs causing esophagitis

Potassium chloride (KCl), aspirin, naproxen, ibuprofen, tetracycline, doxycycline, clindamycin, alendronate, quinidine, vitamin C, iron

Microbes causing esophagitis Candida, HSV, CMV, Mycobacterium tuberculosis

Menetrier’s disease or chronic hypertrophic gastritis

It is characterized by excessive hyperplasia of the gastric mucosa. It is marked in the gastric fundus and body. On gross examination, the gastric rugal folds look prominent. Microscopic features include corkscrew shaped , hyperplastic gastric pits which become dilated forming cystic spaces, thickened mucosa, mild inflammatory infiltrate, atrophy of oxyntic glands, variable edema, hypertrophic muscularis mucosae and lymphoid follicles. It presents with dyspepsia, hematemesis and melena, hypoproteinemia, edema and hypochlorhydria. CMV infection may be associated. Some cases may progress to gastric adenocarcinoma.

Drugs causing peptic ulcers

• NSAIDS
• Steroids
• Aspirin
• Bisphosphonates
• KCl
• Histamine
• Fluorouracil
• Clopidogrel
• Crack cocaine

Cushing’s ulcers: Peptic ulcers in head injury

Curling’s ulcers: Peptic ulcers in burns

Cameron ulcers: Peptic ulcers in hiatal hernia

Alarm symptoms in peptic ulcer disease

• Anorexia, weight loss - cancer
• Vomiting - obstruction
• Anemia, melena, hematemesis - bleeding
• “Boring” abdominal pain radiating to back, rigidity - perforation

NSAIDS and peptic ulcers

NSAIDS cause gastroduodenal ulceration by multiple mechanisms. NSAIDS block the gastrointestinal enzyme COX 1 which leads to decreased prostaglandin synthesis, impairment of mucosal barrier, topical irritation and gastritis, decreased gastric mucosal blood flow, decreased bicarbonate formation and interference with mucosal repair. Gastric acid and proteolytic pepsin then damage the gastroduodenal tissues. Toxicity is higher in the presence of risk factors like age>65 years, heart disease, other ulcer inducing drugs etc. Naproxen and indomethacin have the highest risk while ibuprofen has lower risk.

Histological types of gastric adenocarcinoma

Intestinal

• Prominent gland formation
• No deep infiltration, rather superficial spread
• Secondary to intestinal metaplasia in chronic atrophic gastritis
• Signet-ring cells filled with mucin may be seen

Diffuse

• Cancer cells diffusely infiltrate stroma
• Gland formation not prominent
• Deeper infiltration
• Arise de novo
• Bad prognosis, younger age group

Dermatitis herpetiformis: It presents as extremely itchy blisters (herpetic), eczematous rash with clusters of papules and vesicles seen on the extensor surface of the elbows, knees, buttocks, back or scalp. Scratch marks can be seen from intense itching. It is triggered by IgA deposits in skin formed against epidermal transglutaminase in celiac disease. Microscopy shows microabscesses filled with neutrophils and eosinophils. Remedy is with a gluten-free diet and dapsone.

Malabsorptive diarrhea: It is diarrhea associated with impaired nutrient absorption and digestion. It presents with bloating and pale, bulky, foul smelling, fatty stools (difficult to flush, tend to float). Malabsorptive diarrhea is seen in cystic fibrosis, celiac disease, intestinal bypass surgery, mesenteric ischemia, blind loop or small bowel bacterial overgrowth syndrome, pancreatic disease, Whipple disease and giardiasis.

Obturator sign: It is pain in RLQ on flexion and internal rotation of the hip. It is due to irritation of the obturator internus muscle by an inflamed pelvic appendix.

Psoas sign: It is pain in RLQ with extension of the right hip or with flexion of the right hip against resistance. It is caused by irritation of the iliopsoas muscle by an inflamed appendix. It may also be seen in psoas abscess or retroperitoneal hemorrhage.

Appendicitis with a mass in RLQ: The presence of a mass is suggestive of an abscess or phlegmon. Following rupture of the appendix, the omentum and surrounding bowel may adhere to it, in an effort to wall-off the perforation which can be palpated as an appendicular mass. If the patient is stable and a mass is seen on imaging, then conservative management is preferred with IV antibiotics and percutaneous or transrectal drainage of any localized abscess. This is followed by interval appendicectomy 4-8 weeks later.

Toxic megacolon or toxic colitis: It is a potentially fatal condition characterized by abnormal dilation of the colon from severe colitis. It presents with fever, abdominal pain and distension, nausea, vomiting,shock, diarrhea with/without blood and mucus, mental status changes and decreased bowel sounds. There is a high risk of perforation and peritonitis. It can occur as a complication of ulcerative colitis, less commonly in Crohn’s disease, or any other severe colitis from ischemia, infection, radiation, drugs like opioids and anticholinergics or pseudomembranous colitis. In UC, extension of inflammation into the muscularis layer and deeper into the colonic wall, along with tissue damage by neutrophil enzymes and increased local synthesis of nitric oxide lead to toxic megacolon. Imaging studies like X ray or CT scanning show colonic dilation, multiple air-fluid levels, >6cm dilation of the transverse colon. Endoscopy is contraindicated in suspected toxic megacolon due to high risk of perforation. Treatment involves supportive therapy, bowel rest, nasogastric tube, antibiotics (vancomycin and metronidazole), steroids and surgery like subtotal colectomy with ileostomy, sigmoidostomy or rectostomy. Not all cases need surgery.

Angiodysplasia (vascular ectasia) of the colon: It is a vascular malformation most commonly found in the cecum and ascending colon. It is a common cause of painless, lower gastrointestinal bleeding in the elderly. Lesions may be single or multiple. They are associated with chronic renal disease, aortic stenosis, von Willebrand disease, scleroderma etc. It is diagnosed by endoscopy, enteroscopy and angiography which shows a vascular tuft and early opacification of the draining veins. Technetium 99m or Tc sulfur colloid scan can detect active bleeding from angiodysplasia. Microscopically, clusters of dilated blood vessels are seen in the mucosa and submucosa. It is treated with endoscopic coagulation, angiographic embolization or right colectomy, depending on the severity. Bleeding stops spontaneously in most cases.

Genes involved in progression of adenoma to colon cancer

• Proto-oncogenes: K-ras, MYC
• Tumor suppressor genes: APC, DCC, p53
• DNA repair genes: MLH1, MSH2, MSH6

Cronkite-Canada syndrome: It is an acquired polyposis syndrome that presents with polyps in the gastrointestinal tract along with diarrhea, vomiting, protein losing enteropathy, alopecia, cutaneous pigmentation and onycholysis. Rarely, polyps may become malignant.

Goodsall rule for anorectal fistulas: It helps in planning fistula surgery by determining the tract of a fistula by correlating the position of the external opening of a fistula to an imaginary line drawn from 3 o’clock to 9 o’clock position across the anal verge. If the opening is anterior to the line then the fistula follows a radial or straight path into the anal canal while if the opening is posterior then the tract follows a curved path to open into the anal canal.

Grades of internal hemorrhoids

• Grade I: Hemorrhoids project into the anal canal but do not prolapse below the anal verge
• Grade II: Protrude below the anal verge on straining but reduce spontaneously
• Grade III: Need to be reduced manually
• Grade IV: Chronically prolapsed, irreducible

Jaundice in the newborn period: Most cases of newborn jaundice are physiological. Catabolism of hemoglobin is high in the newborn period due to which more bilirubin is produced. Due to relative immaturity of hepatic glucuronyl transferase enzyme, the levels of unconjugated bilirubin are elevated. Physiological jaundice is first seen on days 2-4 after birth and resolves by 2 weeks. Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL/day or is higher than 17 mg/dL or an infant has signs and symptoms suggestive of serious illness. Unconjugated bilirubin carries a high risk of CNS damage by depositing in the basal ganglia and brainstem nuclei . It can present as encephalopathy which may progress to kernicterus. Bilirubin encephalopathy presents with jaundice, lethargy, high-pitched cry, and poor feeding. Kernicterus is a more severe form presenting as opisthotonus, cerebral palsy, hearing loss, paralysis of upward gaze and mental retardation. The management of mild neonatal jaundice is by increasing breast feedings, supplemented with formula feeding if needed; cases with high elevations of serum bilirubin should be treated with phototherapy and exchange transfusion. CNS symptoms must be treated emergently with exchange transfusion.

Cut-off levels for starting phototherapy in newborns*

Age	Bilirubin level
25-48 hours	15 mg/dl
49-72 hours	18 mg/dl
>72 hours	20 mg/dl

* In sick infants with jaundice, phototherapy should be started even if bilirubin levels are lower

Fatty liver

It is the accumulation of lipids, mainly triglycerides, in the hepatocytes.

Causes of fatty liver

• Obesity
• Hyperlipidemia
• Diabetes Mellitus
• Alcoholic liver disease
• Starvation
• Severe malnutrition
• Pregnancy
• Hypoxia
• Toxins like carbon tetrachloride, chloroform, aflatoxins
• Medications like aspirin, halothane, steroids, amiodarone, diltiazem, tamoxifen

Biopsy shows microvesicular steatosis in the initial stages and then macrosteatosis. Hepatocytes are ballooned with lipid deposits in the cytoplasm and nucleus is pushed to the periphery. Mallory bodies are present. It is seen as a vacuole in H and E sections and stained red with Sudan III and Oil Red-O.

Pathogenesis of alcohol induced fatty liver

Alcohol metabolism increases NADH in the liver resulting in an increased NADH/NAD ratio. This leads to increased ketogenesis and fatty acid synthesis and decreased beta oxidation of fatty acids.

Sterol regulatory element-binding proteins or SREBPs are a family of transcription factors that regulate the enzymes responsible for the synthesis of cholesterol, fatty acids and triglycerides in liver and other tissues. Ethanol increases SREBP regulated transcription of the protein SREBP 1 and hepatic triglyceride synthesis.

Alcohol also inhibits PPAR alpha activity. PPAR alpha is a nuclear hormone receptor and stimulates oxidation of fatty acids.

Alcohol inhibits the synthesis of phosphatidylcholine thereby inhibiting VLDL synthesis. As a result, triglyceride secretion from the liver in the form of VLDL is interrupted.

Effect of cirrhosis on other organ systems+

Cirrhotic cardiomyopathy: Impaired systolic function, diastolic dysfunction and prolonged QT interval in the absence of primary cardiac disease; raised BNP and proBNP and troponin; defect in beta receptor activity, myocyte apoptosis, increased nitric oxide and carbon monoxide. Liver transplant is definitive treatment.

Hepatopulmonary syndrome: It is a syndrome characterized by hypoxia, pulmonary vasodilation and liver dysfunction seen in cirrhosis. Liver transplant may help mild to moderate cases.

Portopulmonary hypertension: It is defined as pulmonary hypertension as a result of portal hypertension. There is risk of pulmonary vascular thrombosis. Treatment is with epoprostenol, bosentan, ambrisentan, sildenafil, iloprost, liver transplant.

+ Hepatorenal syndrome also

** Mnagement of cirrhosis complications**

Complication	Management
Bleeding varices	Control bleeding with sclerotherapy, band ligation (preferred); treat hypotension and hypovolemia; octreotide, terlipressin or vasopressin; TIPSS or surgical shunts; temporary balloon tamponade with Sengstaken-Blakemore tube; beta blockers like propranolol or nadolol for prophylaxis
Ascites	Diuretics (furosemide or spironolactone), low sodium diet (limit salt intake to 2000mg/dl, not less), paracentesis, TIPSS
Spontaneous bacterial peritonitis	Treat ascites, iv antibiotics
Renal failure	Treat hypovolemia, maintain adequate hydration, stop diuretics, give albumin infusions, add terlipressin or midodrine and octreotide in hepatorenal syndrome
Encephalopathy	Lactulose, oral Rifaximin, neomycin, metronidazole; treat underlying infections, bleeding, limit protein intake up to 1.5 g/kg/day, correct electrolytes, avoid sedatives, use probiotics

Spontaneous bacterial peritonitis (SBP): It is an infection of ascitic fluid that is seen in cirrhosis and is not associated with other causes of infection like bowel perforation. If another cause of infection is present, it is called secondary bacterial peritonitis. SBP results from compromised host defenses, bacteremia, intrahepatic shunting of colonized blood and decreased bactericidal activity. Patients with severe liver disease indicated by a Child-Pugh class C or above, are at high risk of SBP. It presents with abdominal tenderness, mental status changes, fever, chills, nausea and vomiting. In some patients, it may be asymptomatic, detected only on ascitic fluid examination. Paracentesis with microscopy and culture of ascitic fluid is done. An ascitic fluid neutrophil count > 250/mm3 is taken as cutoff for diagnosis. Infection is monomorphic, meaning it is not caused by mixed flora but by one species of microbes. E.coli, Klebsiella, Streptococci and Enterococci are the commonly implicated organisms. Empiric treatment can be started with cefotaxime or third generation cephalosporins. Final regimen is guided by results of culture and sensitivity. Antibiotics should be started preferably after paracentesis. Adding albumin infusion also helps. Norfloxacin, ciprofloxacin or trimethoprim/sulfamethoxazole can be used for prophylaxis.

Secondary bacterial peritonitis: Secondary bacterial peritonitis results from intra abdominal lesions like perforated bowel, bowel ischemia and necrosis, leaking anastomosis, penetrating abdominal injuries or peritoneal instrumentation like dialysis catheters. Clinically it resembles spontaneous bacterial peritonitis and has neutrophil count > 250 cells/mm3. Bacteriologically, secondary peritonitis is from mixed flora like a combination of E.coli, Klebsiella, Bacteroides etc. It also has higher protein and LDH , and lower glucose (<50mg/dl) than SBP.

Common sites of porta-caval anastomosis in PHT

Site	Vessels involved
Lower esophagus	Esophageal branch of left gastric vein with esophageal branches of azygous/hemiazygous vein
Umbilicus	Paraumbilical vein which drains into left branch of portal vein with superficial epigastric vein (systemic)
Rectal	Superior rectal (portal) with middle and inferior rectal (systemic)

The Child-Pugh score and Model for End Stage Liver Disease (MELD) score are used to predict prognosis of patients diagnosed with cirrhosis. They are used to make decisions regarding benefit versus risk of TIPS or surgical shunts and liver transplantation.

Child-Pugh* Score

Points	1	2	3
Encephalopathy	None	Minimal	Advanced
Ascites	Absent	Controlled	Refractory
Bilirubin (mg/dl)	<2	2-3	>3
Albumin (g/L)	>35	28-35	<28
Prothrombin (sec)	<4 (<1.7)	4-6 (INR 1.7-2.2)	>6 (INR >2.2)

* Also called CTP or Child-Turcotte-Pugh scoring system

From the above table, patients are grouped into three classes. Higher class or score indicates more severe liver disease.

Class A: Patients scoring <7 points, better prognosis

Class B: Patients scoring 7-9 points, bad prognosis

Class C: Patients scoring > or = 10 points, worse prognosis

Values used for MELD score calculation

• Serum bilirubin
• Serum creatinine
• INR

The actual MELD score is then calculated using the following formula.

MELD = 3.8 X log e(total bilirubin [mg/dL]) + 11.2 X log e(INR) + 9.6 X log e(creatinine [mg/dL])

Patients with MELD scores above 40 have >71% mortality in the next 3 months. Patients with MELD score at or above 19 should be referred for liver transplant evaluation. Those with MELD scores >12 should be started prophylaxis for SBP.

Liver transplantation: Either the whole or part of liver can be transplanted. Liver transplants are from cadavers (more common) or living donors. Right lobe transplants including segments 5,6,7 and 8 are more common among segmental transplants. The United Network for Organ Sharing (UNOS) classifies patients using the MELD scoring system if they are aged 12 years or older, or the Pediatric End-Stage Liver Disease (PELD) scoring system if they are younger than 12 years.

UNOS or United Network for Organ Sharing lays down criteria that determines which patients get priority for liver transplant. They are as follows:

Status 1: Patients with acute severe disease who are in ICU with acute liver disease with a life expectancy without a liver transplant of fewer than 7 days, or who recently received a liver transplant and that failed. Status 1 patients get highest priority.

MELD or PELD (pediatric) score: Predicts mortality risk within a 3 month period. Priority is given to patients with higher MELD scores and longer time on the waiting list.

Priority is given first to status 1, followed by higher score on MELD or PELD.

Contraindications of liver transplantation*

• Current untreated infections like SBP

• Advanced, undertreated cardiopulmonary disease

• Alcohol or substance abuse

• Secondary metastases to liver

  Hepatocellular carcinoma is not a contraindication to liver transplant except in advanced stages.

Metastatic tumors of the liver: The liver is a common site for cancer metastases owing to high vascularity and dual blood supply from systemic and portal circulations. Most common metastases are from adenocarcinoma of the colon, followed by pancreatic and breast cancers. Metastases are more common than primary malignancies of the liver. Treatment is with surgical resection, if possible, and chemotherapy.

CEA (carcinoembryonic antigen) and CA 19-9 are used as tumor markers for colon cancers.

Caroli disease: It is a rare syndrome occurring sporadically or sometimes inherited in AR or AD manner. It is characterized by abnormally dilated intrahepatic bile ducts and renal cysts, cholestasis, pruritus, abdominal pain, stones in the bile ducts and symptoms of cholangitis. Rarely, Caroli disease is accompanied with ADPKD. It is called Caroli Syndrome when accompanied by liver fibrosis and portal hypertension. Caroli syndrome is inherited as AR and is often associated with AR polycystic kidney disease. There is increased risk of cholangiocarcinoma. Ultrasound, MRCP and ERCP can be used for diagnosis. Treatment is supportive, some cases may need hepatic lobectomy and transplantation.

Porcelain gallbladder: It is a calcified gallbladder. It carries a high risk of progression to malignancy. It results from chronic cholecystitis. Precipitation of calcium salts in the mucosa due to obstruction to bile flow or calcification from chronic inflammation are the causative factors. Most patients are asymptomatic, though there may be a history of recurrent biliary colic. Management is by cholecystectomy.

Mirizzi syndrome: It is a rare disorder caused by external compression of the common bile duct or common hepatic duct by gallstones in the Hartman’s pouch of the gallbladder. It may result in a cholecysto-choledochal fistula or a cholecysto-enteric fistula with gallstone ileus. Clinical presentation is of biliary colic with obstructive jaundice. Ultrasound shows a gallstone(s) impacted in the gallbladder infundibulum and external obstruction of the CBD with consequent dilation of the intrahepatic biliary tree. CT or MRI should be performed for confirmation. Treatment is with total or partial cholecystectomy, ERCP with stenting or hepaticojejunostomy, depending on severity.

Ranson’s criteria for predicting prognosis of acute pancreatitis

At admission

• Age > 55 years
• WBC count >16,000/microl
• Blood glucose > 200mg/dl
• Serum LDH > 350 IU/L
• Serum AST > 250 IU/L

48 hours after admission

• Decrease in hematocrit > 10%
• Increase in BUN > 8mg/dL
• Serum calcium < 8mg/dL
• PaO2 < 60mmHg
• Base deficit > 4 meq/L
• Fluid sequestration > 6L

Each of the above criteria carries 1 point

Score < 3 mortality 0-3% Score >= 3 mortality 11-15% Score >= 6 mortality 40% or higher

Alternatively, APACHE II scoring system can be used. A score higher than 8 indicates severe pancreatitis.