Scleroderma is a connective tissue disorder that ranges in severity and progression. The disease could show generalised skin thickening with rapid, fatal, visceral involvement; or only cutaneous involvement (typically fingers and face). The slow progressive form is also known as ‘limited cutaneous scleroderma’ or CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, (o)oesophageal dysmotility, sclerodactyly, and telangiectasia).

Sclerosing cholangitis along with the passage of blood in stools suggests ulcerative colitis affecting the mucosa and submucosa of rectum and colon, with a sharp demarcation with the normal tissue. The musclaris layer is involved in severe cases. Initially, the mucosa is erythematous, friable with scattered haemorrhagic areas and loss of normal vascular pattern. Severe disease is indicated by presence of large mucosal ulcers with purulent exudate. There can be islands of normal mucosa between the ulcerated mucosa, along with few hyperplastic inflammatory mucosal lesions (pseudopolyps). Ulcerative colitis does not lead to development of fistulas or abscesses.

Aflatoxins are naturally occurring toxins produced by the Aspergillus fungus (most often, A. flavus and A. parasiticus). These organisms are common and their native habitat is soil, decaying vegetation and grains. They can contaminate the grain before harvest or after storage, more likely in high-humidity (at least 7%) or high temperature environment of after stressful conditions like drought. Aflatoxins are mycotoxins and also carcinogenic. They get metabolized in the liver to an epoxide, aflatoxin M1. High exposure can lead to acute necrosis, cirrhosis or liver carcinoma. These substances can cause haemorrhage, acute liver damage, oedema, and alteration in digestion, absorption and/or metabolism of nutrients. Although humans are susceptible to these toxins like all other animals, they have a high tolerance level and hence, rarely develop acute aflatoxicosis. However, children are particularly susceptible to exposure leading to growth impairment and delayed development. Chronic exposure carries a high risk of hepatic cancer, due to intercalation of its metabolite aflatoxin M1 into the DNA and alkylation of the bases because of its epoxide moiety.

Hepatitis A is the most common acute viral hepatitis, more common in children and young adults. It is caused by Hepatitis A virus, which is a single-stranded RNA picornavirus. The primary route of spread of Hepatitis A is the faecal-oral route. Consumption of contaminated raw shellfish is also a likely causative factor. The shedding of the virus in faecal matter occurs before the onset of symptoms and continues a few days after. Hepatitis A does not lead to chronic hepatitis or cirrhosis, and there is no known chronic carrier state. Hence, a biopsy performed after recovery will show normal hepatocellular architecture.

Ascites develops either from:

• • Increased  accumulation
    • Increased capillary permeability
    • Increased venous pressure
    • Decreased protein (oncotic pressure)
  • Decreased clearance
    • Increased lymphatic obstruction

Cause

• Transudate (<30g/L protein) (Systemic disease)
  • Liver (Cirrhosis)
  • Cardiac e.g. RHF, CCF, SBE right heart valve disease and constrictive Pericarditis
  • Renal failure
  • Hypoalbuminaemia (nephrosis)
• Exudate (>30g/L protein) (Local disease)
  • Malignancy
  • Venous obstruction e.g. Budd-Chiari, Schistosomiasis
  • Pancreatitis
  • Lymphatic obstruction
  • Infection (especially TB)

Cirrhosis is disease of the liver that is characterized by fibrosis leading to disorganization of the hepatic architecture. It shows the development of regenerative nodules surrounded by dense fibrotic tissue. Cirrhosis shows non-specific symptoms initially, which include fatigue, anorexia and weight loss. It can later progress to portal hypertension, ascites and liver failure.

Mallory bodies (or ‘alcoholic hyaline’) are inclusion bodies in the cytoplasm of liver cells, seen in patients of alcoholic hepatitis; and also in Wilson’s disease. These pathological bodies are made of intermediate keratin filament proteins that are ubiquinated or bound by proteins like heat chock protein. Being highly eosinophilic, they appear pink on haematoxylin and eosin staining.

Hirschsprung’s disease is characterized by congenital absence of the autonomic plexus (Meissner’s and Auerbach’s plexus) in the intestinal wall. Usually limited to the distal colon, it can occasionally involve the entire colon or even the small bowel. There is abnormal or absent peristalsis in the affected segment, resulting in continuous spasm of smooth muscle and partial/complete obstruction. This causes accumulation of intestinal contents and dilatation of proximal segment. Skip lesions are highly uncommon. This disease is seen early in life with 15% patients presenting in first month, 60% by 1 year of age and 85% by the age of 4 years. Symptoms include severe and complete constipation, abdominal distension and vomiting. Patients with involvement of ultra-short segments might have mild constipation with intervening diarrhoea. In older children, symptoms include failure to thrive, anorexia, and lack of an urge to defecate. On examination, an empty rectum is revealed with stool palpable high up in the colon. If not diagnosed in time, it can lead to Hirschsprung’s enterocolitis (toxic megacolon), which can be fulminant and lead to death. Diagnosis involves a barium enema or a rectal suction biopsy. Barium enema shows a transition in diameter between the dilated, normal colon proximal to the narrowed, affected distal segment. It is to be noted that barium enema should be done without prior preparation, which can dilate the abnormal segment, leading to a false-negative result. A 24-hour post-evacuation film can be obtained in the neonatal period – if the colon is still filled with barium, there is a high likelihood of Hirschsprung’s disease. Full-thickness rectal biopsy is diagnostic by showing the absence of ganglion cells. Acetylcholinesterase staining can be done to highlight the enlarged nerve trunks. Abnormal innervation can also be demonstrated by rectal manometry.

Increased alkaline phosphatase is indicative of cholestasis, with a 4x or greater increase seen 1-2 days after biliary obstruction. Its level can remain elevated several days after the obstruction is resolved due to the long half life (7 days). Increase up to three times the normal level can be seen in hepatitis, cirrhosis, space-occupying lesions and infiltrative disorders. Raised alkaline phosphatase with other liver function tests being normal can occur in focal hepatic lesions like abscesses or tumours, or in partial/intermittent biliary obstruction. However, alkaline phosphatase has several isoenzymes, which originate in different organs, particularly bone. An isolated rise can also be seen in malignancies (bronchogenic carcinoma, Hodgkin’s lymphoma), post-fatty meals (from the small intestine), in pregnancy (from the placenta), in growing children (from bone growth) and in chronic renal failure (from intestine and bone). One can differentiate between hepatic and non-hepatic cause by measurement of enzymes specific to the liver e.g. gamma-glutamyl transferase (GGT).

In an elderly, asymptomatic patient, isolated rise of alkaline phosphatase usually points to bone disease (like Paget’s disease). Presence of other symptoms such as jaundice, pale stools, weight loss suggests obstructive jaundice, most probably due to pancreatic carcinoma.

Hepatocellular carcinoma or hepatoma affects people with pre-existing cirrhosis and is more common in areas with higher prevalence of hepatitis B and C. Diagnosis include raise alpha-fetoprotein levels, imaging and liver biopsy if needed. Patients at high-risk for developing this disease can undergo screening by periodic AFP measurement and abdominal ultrasonography. The malignancy carries poor prognosis (see also Answer to 10.4).

Primary sclerosing cholangitis is characterised by patchy inflammation, fibrosis and strictures in intra- and extra-hepatic bile ducts. It is a chronic cholestatic condition with 80% patients having associated inflammatory bowel disease (likely to be ulcerative colitis). Symptoms include pruritus and fatigue. ERCP (endoscopic retrograde cholangiopancreatography) or MRCP (magnetic resonance cholangiopancreatography) are diagnostic. Disease can lead to complete obliteration of ducts, which can result in liver failure. Cholangiocarcinoma is also a recognised complication..