The initial manifestation of MEN2 was medullary thyroid carcinoma in 60% of patients, medullary thyroid carcinoma synchronous with pheochromocytoma in 34% and pheochromocytoma alone in 6%. 72% had bilateral pheochromocytomas. Causes
The table in the multiple endocrine neoplasia article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin. A database of MEN-implicated RET mutations is maintained by the University of Utah Department of Physiology.The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET gene can have effects in nervous tissues throughout the body. MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM # 164761 lists the syndromes associated with the RET gene. Genetics
When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.
It may manifest as a very high level of ALT and severe disturbance of liver function leading to acute liver failure. Causes include:
Paracetamol, carbon tetrachloride

Hepatitis
In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically. Causes:
(a) Viral hepatitis: Halothane, isoniazid, phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac

Cholestasis
Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (vanishing duct syndrome). Causes:
(a) Bland: Oral contraceptive pills, anabolic steroid, androgens
(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine
(c) Ductal: Chlorpromazine, flucloxacillin

Steatosis
Hepatotoxicity may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease)

Causes:
(a) Microvesicular: Aspirin (Reyes syndrome), ketoprofen, tetracycline (especially if expired)
(b) Macrovesicular: Acetaminophen, methotrexate
(c) Phospholipidosis: Amiodarone, total parenteral nutrition
(d) Antiviral: nucleoside analogues
(e) Corticosteroid
(f) Hormonal: Tamoxifen

Granuloma
Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity.