Diseases of the liver and pancreas

Tumors: Non-Neoplastic Cysts

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  Cysts of the pancreas are infrequent
  
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  Congenital cysts: Result from anomalous development of the pancreatic ducts.
  
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  Congenital polycystic disease: Cysts coexisting in the kidney, liver, and pancreas
  
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  Von Hippel-Lindau disease:
  

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  Angiomas found in the retina and cerebellum or brain stem
  
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  Associated cysts in the pancreas, liver, and kidneys
  

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  Cysts lined by a smooth, glistening membrane that may exhibit
  

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  Ductal-type cuboidal epithelium
  
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  Completely atrophic, attenuated cell layer.
  

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  Cysts usually enclosed in a thin, fibrous capsule
  
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  Filled with a clear-to-turbid mucoid or serous fluid
  

Pseudocysts

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  Are localized collections of pancreatic secretions that develop following
  

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  Inflammation of the pancreas - acute / chronic (commonest)
  
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  Traumatic injury to the abdomen
  

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  Are to be distinguished from sterile pancreatic abscesses,
  

-liquefactive necrosis of severely damaged pancreatic parenchyma.

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  Both entities lack a true epithelial lining, unlike congenital cysts..
  
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  Clinical Features:
  

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  Abdominal pain
  
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  Hemorrhage
  
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  Infection
  
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  Generalized peritonitis
  

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  Are usually unilocular distinguishing them from neoplastic cysts,
  

which tend to be multiloculated
Tumors - Neoplastic Cysts

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  Comprise 5% of all pancreatic neoplasms Mucinous cystadenoma of Pancreas
  
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  Are usually located in the body or tail
  
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  Present as painless, slow-growing masses.
  

Mucinous cystic tumors:

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  Multiloculated, cystic neoplasms filled with mucinous secretions
  

resembling their histologic counterpart in the ovary

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  Mucinous cystadenoma: Benign
  
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  Cystadenocarcinoma: Malignant
  

Microcystic adenoma:

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  A rare cystic tumor with serous secretions
  
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  Is almost always benign.
  

Papillary-cystic tumor:

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  Solid-cystic predominantly in adolescent girls and women < 35 years of age.
  
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  Is a large, rounded, well-circumscribed mass that has solid and cystic zones.
  
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  Histologically:
  

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  Tumor cells are small and uniform
  
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  Have a finely granular eosinophilic cytoplasm
  
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  Grow in solid sheets or papillary projections
  

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  Cause abdominal discomfort and pain
  
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  Treatment: Resection.
  

Carcinoma of the Pancreas

Most frequent causes of death from cancer in the US

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  Lung
  
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  Colon
  
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  Breast
  
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  Prostate
  
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  Pancreas
  
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  Arising in the exocrine portion of the gland.
  
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  Almost all are adenocarcinoms arising in the
  

ductal epithelium

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  Causation – unknown
  
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  Strong association with smoking
  
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  Inconsistent risk factors:
  

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  Chronic alcohol intake
  
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  High energy diets rich in fat
  
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  May arise anywhere in the pancreas:
  

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  Head of pancreas - 60%
  
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  Body of pancreas - 15 to 20%
  
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  Tail of pancreas - 5%
  

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  Cancer of the head of the pancreas can impinge on :
  

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  Ampulla of Vater
  
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  Common bile duct
  
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  Duodenum
  

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  Can cause obstructive biliary symptoms relatively early in their life history
  

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  May be discovered before widespread metastasis has occurred
  

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  Cancers of the body and tail may grow silently until such time as extension to adjacent structures and metastatic dissemination preclude surgical intervention
  

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  Histologic appearance:
  
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  Poorly differentiated adenocarcinoma forming abortive tubular structures or cell clusters
  
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  Exhibit an aggressive, deeply infiltrative growth pattern
  
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  Dense stromal fibrosis accompanies tumor invasion
  
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  Proclivity for perineural invasion within and beyond the organ
  
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  Well to moderately differentiated tumors are the exception.
  

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  Normal Acinar Structure (Right)
  
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  Adenocarcinoma (Left)
  

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  Low power microscope
  

Clinical Features

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  Are insidious lesions
  
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  Present for months and possibly years before they produce symptoms referable to their expansive growth.
  
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  Major symptoms include :
  
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  Weight loss
  
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  Abdominal pain
  
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  Back pain
  
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  Anorexia
  
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  Nausea / vomiting
  
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  Generalized malaise
  
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  Weakness
  
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  Jaundice (in 90% of patients with carcinomas of the head)
  
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  Migratory thrombophlebitis, known as Trousseau’s syndrome
  
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  Occurs in 10% of patients
  
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  Attributed to the elaboration of platelet-aggregating factors and procoagulants from the tumor or its necrotic products
  

Laboratory Diagnosis:

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  Elevated levels of CEA and CA 19-9 antigen
  

Treatment:

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  Surgical – Whipple’s procedure
  

Prognosis:

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  Poor
  
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  One-year survival < 20%
  
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  5-year survival 3%
  

The Endocrine Pancreas

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  The endocrine pancreas consists of about 1 million microscopic cellular units–the islets of Langerhans
  
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  Consist of four major and two minor cell types.
  
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  The four main types are
  
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  B (beta) -produce insulin (maximum in number – 70%)
  
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  A (alpha)
  

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  Account for 20% of all the islet cells
  
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  Secrete glucagon
  
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  Glucagon induces hyperglycemia by its glycogenolytic activity in the liver
  

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  D cells (delta) – 5-10% contain somatostatin, which suppresses both insulin and glucagon release
  
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  PP (pancreatic polypeptide) cells - 1 to 2%, respectively, of the islet cell population. contain a unique pancreatic polypeptide that exerts a number of gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility
  
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  The two rare cell types are
  
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  D1 cells elaborate vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and hyperglycemia and also stimulates gastrointestinal fluid secretion and causes secretory diarrhea
  
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  Enterochromaffin cells. synthesize serotonin and are the source of pancreatic tumors that induce the carcinoid syndrome.
  

Diabetes Mellitus

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  It is a chronic disorder of carbohydrate, fat and protein metabolism
  
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  Characteristic feature: A defective or deficient insulin secretory response resulting in impaired carbohydrate use and hyperglycemia
  
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  Diabetes mellitus represents a heterogenous group of disorders that have hyperglycemia as a common feature
  
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  Can be
  

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  Primary
  
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  Secondary
  

Classification of Diabetes

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  Insulin-dependent diabetes mellitus (IDDM), also called type I diabetes /Juvenile-onset and Ketosis-prone diabetes.
  

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  Accounts for about 10 to 20% of all cases
  

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  Non-insulin dependent diabetes mellitus (NIDDM), also called type II diabetes / adult-onset diabetes
  

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  Accounts for 80 to 90% of cases
  

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  A third rare form, known as maturity-onset diabetes of the young (MODY).
  

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  MODY is manifested by mild hyperglycemia
  
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  Transmitted as an autosomal dominant trait.
  
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  Accounts for < 5% of the cases
  

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  The two major types of diabetes have different pathogenetic mechanisms and metabolic characteristics
  
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  However, the chronic, long-term complications in blood vessels, kidneys, eyes, and nerves occur in both types
  
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  Complications are the major cause of morbidity / death in diabetes
  

Table: exam:

IDDM (type I)

Islet cell antibodies

HLA-D linked

Severe insulin deficiency

NIDDM (type II)

Insulin resistance

Mild-beta-cell depletion

Morphology of Diabetes and its Late Complications

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  Morphologic changes in diabetes are responsible for many late systemic complications
  
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  There is extreme variability among patients in :
  

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  Time of onset
  
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  Severity of these complications
  
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  Particular organ or organs involved
  

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  Regardless of the type of diabetes, when the disease has been present for 10 to 15 years, morphologic changes are likely to be found in :
  

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  Basement membranes of small vessels (microangiopathy)
  
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  Arteries (atherosclerosis)
  
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  Kidneys (diabetic nephropathy)
  
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  Retina (retinopathy)
  
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  Nerves (neuropathy)
  

Morphology of Pancreas - Islet Changes

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  Lesions in the pancreas are neither constant nor necessarily pathognomonic
  
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  More likely to be distinctive in type I than in type II
  
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  One or more of the following alterations may be present:
  
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  Reduction in the size and number of islets
  
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  Leukocytic infiltration of the islets
  

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  Insulitis: Is a heavy lymphocytic infiltrate within and about the islets
  
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  Eosinophilic infiltrates may also be found
  

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  Beta-cell degranulation
  
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  Amyloid replacement of islets
  
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  Increase in the size and number of islets
  

Diabetic Microangiopathy

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  One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes.
  
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  It is most evident in the capillaries of the skin, skeletal muscles, retina, renal glomeruli, and renal medulla, giving rise to the characteristic diabetic microangiopathy of these organs.
  
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  Microangiopathy is clearly related to the hyperglycemia.
  
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  Hyaline arteriolosclerosis is both more prevalent and more severe in diabetics than in nondiabetics.
  

Atherosclerosis

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  Increased rate of atherosclerosis
  
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  Arterial narrowings or occlusions and attendant ischemic injury to organs
  
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  May induce aneurysmal dilatation, seen most often in the aorta, with the grave potential of rupture.
  
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  Myocardial infarction, cerebral stroke, and gangrene of the lower extremities in these patients.
  

Diabetic nephropathy

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  Renal artery atherosclerosis
  
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  Arteriolosclerosis
  
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  Glomerulosclerosis
  

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  Diffuse
  
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  Nodular- Kimmelstiel- Wilson disease
  

Nodular Glomerulosclerosis

Diabetic Ocular Complications

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  Development of visual impairment consequent to
  

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  Retinopathy
  
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  Cataract formation
  
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  Glaucoma
  

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  In the development of diabetic retinopathy, the duration of disease appears to be a very important determinant.
  

Diabetic Retinopathy

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  Retinopathy takes two forms:
  

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  Nonproliferative, or background, retinopathy
  
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  Proliferative retinopathy.
  

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  Nonproliferative, or background, retinopathy includes:
  

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  Intraretinal or preretinal hemorrhages
  
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  Retinal exudates
  
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  Thickening of the retinal capillaries (microangiopathy)
  
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  Development of microaneurysms.
  

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  Proliferative retinopathy is associated with
  

neovascularization and fibrosis.

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  Neovascularization at periphery
  
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  Small hemorrhages
  

Diabetic Neuropathy

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  Peripheral nerves, brain, and spinal cord all may be damaged in long-standing diabetes.
  
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  Most commonly encountered is symmetric peripheral neuropathy affecting both motor and sensory nerves of the lower extremities.
  
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  It is characterized by Schwann cell injury, myelin degeneration, and also axonal damage.
  
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  The peripheral neuropathy is sometimes accompanied by disturbances in the neural innervation of the pelvic organs (autonomic neuropathy), leading to
  

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  Sexual impotence
  
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  Bowel and bladder dysfunction.
  

Islet Cell Tumors

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  Are rare in comparison with tumors of the exocrine pancreas
  
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  Are most common in adults
  
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  Can occur anywhere along the length of the pancreas
  
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  May be hormonally functional / nonfunctional
  
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  May be single / multiple
  

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  When multiple, each tumor may be composed of a different cell type
  

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  Benign / malignant
  

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  Metastasize to lymph nodes and liver
  

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  Three most common and distinctive clinical syndromes associated with hyperfunction of the islets of Langerhans are:
  

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  Hyperinsulinism (Insulinoma)
  
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  Zollinger-Ellison syndrome (gastrinoma)
  
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  Multiple endocrine neoplasia.
  

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  Each of these may be caused by :
  

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  Diffuse hyperplasia of the islets of Langerhans
  
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  Benign adenomas that occur singly or multiply
  
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  Malignant islet tumors
  

Beta-Cell Tumors (Insulinoma)

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  Are the most common of islet cell tumors
  
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  Elaboration of insulin to induce clinically significant hypoglycemia
  
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  Characteristic clinical triad resulting from these pancreatic lesions:
  

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  Attacks of hypoglycemia
  
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  Attacks consist of central nervous system manifestations as
  

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  Confusion
  
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  Stupor
  
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  Loss of consciousness
  

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  Related to fasting or exercise
  
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  Promptly relieved by the feeding or parenteral administration of glucose.
  

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  Laboratory findings : High circulating levels of insulin and a high insulin-to-glucose ratio.
  
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  Surgical removal of the tumor is usually followed by prompt reversal of the hypoglycemia.
  

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  A variety of functional and organic disorders, in addition to the beta-cell lesions, cause hypoglycemia:
  
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  These include :
  

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  Early diabetes mellitus
  
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  Partial gastrectomy
  
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  Starvation
  
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  Diffuse liver disease
  
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  Glycogenoses
  
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  Hypofunction of the anterior pituitary
  

and adrenal cortex

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  Variety of extrapancreatic neoplasms
  
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  Idiopathic hypoglycemia.
  

Morphology

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  Of all insulinomas:
  

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  ~70% are solitary adenomas
  
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  ~10% are multiple adenomas
  
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  ~10% are metastasizing tumors that must be interpreted as carcinomas
  
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  remainder are a mixed group of diffuse hyperplasia of the islets and adenomas occurring in ectopic pancreatic tissue.
  

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  Insulinomas vary in size from minute lesions that are difficult to find even on the dissecting table to huge masses of over 1500 gm
  
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  Grossly: Are usually encapsulated, firm, yellow-brown nodules,
  
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  Histologically: Composed of cords and nests of well-differentiated beta cells that do not differ from those of the normal islet
  
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  On electron microscopy: Tumor cells exhibit beta-cell granules
  
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  Immunohistochemistry: insulin can be visualized in tumor cells.
  
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  Five per cent of insulinomas are malignant.
  

Zollinger-Ellison Syndrome (Gastrinoma)

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  Syndrome classically composed of the triad of
  

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  Recalcitrant peptic ulcer disease
  
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  Gastric hypersecretion
  
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  Pancreatic islet cell tumor
  

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  Fundamental to peptic ulcerations is gastric hypersecretion, induced by gastrin, so the tumor is also known as a gastrinoma.
  
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  Although most common in the pancreas, 10 to 15% of gastrinomas occur in the duodenum.
  
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  Serum gastrin levels are elevated
  
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  ~ 60% of gastrinomas are malignant, and 40% are benign.
  
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  Only spread to lymph nodes or metastasis marks the tumors as malignant
  

Problems in clinical management:

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  Gastric hypersecretion produces intractable ulcers
  
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  Diarrhea often extreme - causes serious problems in fluid and electrolyte control - development of malabsorption syndromes
  
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  Pancreatic lesions may be very small or multiple - difficult to discover at surgical exploration
  
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  Therefore recurrent symptoms following removal of any apparent solitary lesion with later discovery of additional lesions within the pancreas
  

DISEASES OF THE RENAL SYSTEM

Overview of Renal Diseases

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  Subdivided into
  
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  Congenital diseases
  
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  Renal Cystic Diseases
  
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  Glomerular diseases- most commonly immunologic
  
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  Tubular diseases
  
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  Interstitial diseases- usually combined with tubular as tubulointerstitial-usually due to drug toxicity or infections
  
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  Vascular diseases- most commonly related to hypertension or diabetes
  
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  Obstructive uropathy
  
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  Tumors of the kidney
  

Congenital Anomalies

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  Agenesis
  
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  Hypoplasia
  

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  Kidney fails to develop to it’s normal size
  

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  Ectopic Kidneys
  

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  Developmentally at an abnormal position
  

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  Just above the pelvic brim / within the pelvis
  

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  Horseshoe Kidney
  
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  Cystic Diseases of the Kidney
  

Agenesis of the Kidney

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  Total bilateral agenesis:
  

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  Is incompatible with life
  
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  Is usually encountered in stillborn infants
  
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  Often associated with many other congenital disorders (limb defects, hypoplastic lungs)
  

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  Unilateral agenesis:
  

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  Is compatible with normal life, if no other abnormalities exist.
  
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  Opposite kidney undergoes compensatory hypertrophy
  

Horseshoe Kidney

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  Two kidneys fused at the poles
  
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  Lower poles in 90% (‘pelvic kidney’)
  
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  Upper poles in 10%
  
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  Usually located at the level of the lower lumbar vertebrae
  
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  Ascent is stopped by the root of the inferior
  

mesenteric artery

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  Associated abnormalities of the ureters:
  
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  In their course
  
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  Abnormal openings into the bladder or urethra
  
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  Infections and stone formation are common
  
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  Seen in Turner’s syndrome
  

Cystic Diseases of the Kidneys

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  Cystic renal dysplasia
  
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  Polycystic kidney disease
  
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  Autosomal dominant (adult) polycystic disease
  
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  Autosomal recessive (childhood) polycystic disease
  
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  Medullary cystic disease
  
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  Medullary sponge kidney
  
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  Nephronophthisis—uremic medullary cystic disease (UMCD) complex
  
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  Acquired (dialysis-associated) cystic disease
  
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  Localized (simple) renal cysts
  
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  Renal cysts in hereditary malformation syndromes (e.g., tuberous sclerosis)
  
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  Glomerulocystic disease
  
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  Extraparenchymal renal cysts (pyelocalyceal cysts, hilar lymphangitic cysts)
  

Renal Cystic Disease in Children

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  Oligohydramnios is a clinical feature
  
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  Due to urinary obstruction and absence of fetal urine
  
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  Leads to decrease in the amount of amniotic fluid
  
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  Most syndromes are autosomal recessive
  
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  Cystic renal disease is the MOST COMMON cause of a palpable abdominal mass in a newborn
  
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  Usually infantile polycystic disease or renal dysplas
  

Potter’s Facies

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  Low set ears
  
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  Parrot beak-like nose
  
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  Receding chin.
  

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  Associated with:
  
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  Renal agenesis
  
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  Bilateral renal dysplasia
  
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  Infantile polycystic kidney