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Pathophysiology of
GIT II
Exocrine pancreas
Liver
Biliary tract
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Pathophysiology of exocrine pancreas
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Pancreas - secretion
• endocrine part (2%)
• insulin, glucagon, somatostatin,
gastrin, pancreatic polypeptide,
amylin
• exocrine part (85%) - acines
• pancreatic juice (pH up to 8.3)
• approx. 1-1.5l day
• production stimulated by
acetylcholine, CCK and secretin
produced in duodenum
• production inhibited by pancreatic
polypeptide
• composition
• ions and water (←secretin)
• Na, Cl, K and HCO3
- (up to
150 mmol/l)
• HCO3
- necessary to neutralize
acid content of stomach, for
activation of pancreatic.
enzymes and formation of
micelle
• enzymes (←CCK)
• active - lipase, amylase,
ribonuclease,
deoxyribonuclease
• inactive (activated by
enterokinase in duodenum) -
trypsinogen,
chymotrypsinogen,
prokarboxypeptidase,
proelastase, phospholipase
A2
• inhibitory trypsinu (α1-antitrypsin)
• disorder of secretion – insufficiency
of exocrine pancreas
• most often due to chron. pancreatitis
• carcinoma of pancreas, cystic
fibrosis, protein malnutrition
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Chronic pancreatitis
• chronic inflammation of pancreas
leading to progressive dysfunction of
pancreatic acins, stenosis and dilation of
ducts, fibrosis and atrophy of gland and
calciphications in ducts
• etiology
• hypertriglyceridemia
• hypocalcaemia
• chron. malnutrition
• alcoholism
• tropical form
• hereditarily
• cystic fibrosis
• consequences
• absence of lipase
• maldigestion and malabsorption of fats (→ steatorhea, diarrhea)
• deficiency of lipid-soluble vitamins
• absence of amylase and peptidases
• mostly compensated by stomach and intestinal enzymes, malabsorption of sugars and AA thus
clinically insignificant
• hypocalcaemia and hyperphosphatemia (due to ↓ vit. D)→ osteomalacia
• deficit of vit. B12 (due to deficit of protease its release from dietary sources low)→
anemia
• pain
• secondary diabetes mellitus (destruction of islets of Langerhans)
• complications
• cysts, closure of ducts, leak of juice to peritoneal and pleural cavity
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Cystic fibrosis (mucoviscidosis)
• monogenic (AR) disease due to mutation in gene
encoding “cystic fibrosis transmembrane
conductance regulator” (CFTR)
• >600 known mutations in one of the 4 classes
• I – defective protein (preterm stop of translation of CFTR
mRNA )
• II – increased degradation of protein in endopl. reticulum
(incl. the most common mutation ∆F508 ~70%)
• III – inactivated channel
• IV – defect of transport
• function of CFTR
• encodes a complex protein forming chloride channel
• regulates other channels (e.g. Na)
• CF affects
• epithelia of respiratory tract
• viscous secret, limitation of respiration and coughing,
terrain for infection (Pseudomonas aeruginosa)→ chron.
bronchitis, bronchiectasis, pneumonia
• epithelia in pancreatic ducts
• recycling of Cl involved in secretion of HCO3
- into
pancreatic juice→ due to decreased bicarbonate too
viscose protein secret blocking ducts(chron. pancreatitis)
• sweat glands
• decreased reabsorption of Cl (diagnostic sign - high Cl in
sweat)
• intestine
• meconic ileus of newborns
• liver and biliary tract
• genitals
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• acute destruction of pancreatic tissue and neighboring tissue due to
autodigestion by pancreatic enzymes activated directly in the gland
• very serious and severe condition associated with high mortality
• symptoms
• intensive pain
• nausea and vomiting
• fever
• etiology
• biliary
• blockade by bile stone in common duct
• alcohol
• relaxation of sphincter of Oddi
• reflux of bile into pancreatic duct
• abdominal trauma
• infection
• hypertriglyceridemia
• hypercalcaemia
• drugs
• pathogenesis
• intracellular and extracellular activation of trypsinogen and subsequently of other
enzymes
• cathepsine B in low pH
• autodigestion of gland
• elastase digests elastin in vessel walls→hemorrhage into gland, leak of juice into
circulation and damage of systemic circulation
• lipolysis of pancreas by pancreatic lipase and phospholipase A2
Acute pancreatitis
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Tumors of pancreas
• most commonly adenocarcinoma
• ↑ risk
• chron. pancreatitis
• smokers
• chron. alcoholism
• typically head and body, less often
caudal pancreas
• signs
• obstructive icterus (compression of
biliary duct)
• pancreatic insufficiency
• thrombophlebitis
• very poor prognosis
• tumors of endocrine pancreas
• insulinoma (hypoglycemia)
• gastrinoma (Zollinger-Ellison syndrome)
• VIPoma (diarrhea, hypokalemia)
• carcinoid
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Anatomy and histology of liver
• liver (hepar) ~1.5kg
• 2 lobes (sin. and dx.) divided by ligament
• liver parenchyma has characteristic
architecture
• liver lobule is a basic morphologic unit
• central vein lobule
• peripheral portobiliar “trias”
• liver acinus is basic functional unit
• part of the tissue supplied by branches of
one circumlobular vein
• function of liver
• complex metabolic function
• saccharides
• glycogen synthesis, glycogen lysis,
gluconeogenesis
• lipids
• clearance of lipoproteins, synthesis of
cholesterol, synthesis of TAG
• proteins
• trans- and de-amination of AA, protein
synthesis (albumin, clotting factors)
• formation of bile
• metabolisms of haem
• biotransformation, detoxification
• hormones, drugs, toxins, ammoniac from
intestine
• storage of vitamins and trace
substances
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Liver blood supply
• v. portae (80% of blood supply)
• drainage from splanchnic organs
(= functional supply)
• capillaries from stomach, intestine,
pancreas and spleen connect in portal
vein
• its branches encircle liver lobules (v.
interlobulares and circumlobulares)
• they enter them as liver sinusoids
• sinusoids join to form central vein
• a. hepatica (20% of supply)
• branch of truncus coeliacus
(= nutritional supply)
• drain to sinusoid and then to the
central vein
• v. hepatica
• drainage from liver
• central veins connect to right and left
liver vein leading to lower vena cava
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Liver blood supply
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Morphology of liver - lobule
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Liver lobule schematically
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Liver lobule vs. acinus
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Hepatocytes, liver sinusoids
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REACTION OF LIVER TO
DAMAGE &&&& LIVER DISEASES
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Etiology of liver damage
• infection
• viral
• hepatitis viruses (HAV, HBV, HCV, …)
• inf. mononucleosis (EBV)
• bacterial
• leptospirosis
• parasite
• Echinococcus
• globally, Europe - Mediterranean
• Schistosomiasis (= bilharzias)
• Africa, J. America, Caribbean, SE Asia
• malaria
• toxic
• alcohol
• faloidin (Amanita faloides)
• drugs (e.g. paracetamol)
• chemicals
• autoimmune
• autoimmune hepatitis
• prim. biliary cirrhosis
• metabolic disorders
• common - NAFLD/NASH
• rare
• heredit. hemochromatosis
• Wilson disease
• porphyria
• glycogenosis
• tumors
• primary (hepatocellular carcinoma)
• metastases
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Liver infection - hepatitis
• time course
• acute
• ussually without residual damage
• fulminant form leading to liver failure
• chronic
• only persistent infection (carriers)
• necrosis of parenchyma and progression to
cirrhosis
• viral hepatitis
• hepatitis A (HAV – RNA virus)
• only acute time course
• virus directly cytotoxic
• epidemic
• fecal-oral transmission (vaccination)
• hepatitis B (HBV – DNA virus)
• blood borne (parenteral) and STD
• time course
• virus is not directly cytotoxic, damage is the
results of the reaction of immune system
• mostly acutely without residual damage
• in 10% of cases progresses to chronicity
• either solely HBsAg positive carriers
• or active process leading to fibrosis
and cirrhosis)
• hepatitis C (HCV – RNA virus)
• blood born (parenteral) and STD
• acute phase typically asymptomatic
• more than 80% cases progress to
chronicity – can lead to cirrhosis 18
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Reaction of liver to damage
(Painting: Christian Griepenkerl's
Prometheus Tortured by the Eagle, 1800's)
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Reaction of liver to damage
• liver can react the same way to various etiologies of
damage
• mild damage change metabolic activity of hepatocyte,
which become to cumulate fat (= steatosis)
• steatosis with lab. signs of inflammation is called
steatohepatitis
• more severe damage leads to cell death, however liver
has a considerable ability to regenerate
• long-term damage leads to production of connective
tissue in periportal areas (= fibrosis)
• combination of intensive necrosis, fibrosis and
regeneration significantly altering lobular architecture
is called cirrhosis
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Initial (reversible) liver damage
• steatosis (S)
• normally fat content (TAG) in hepatocytes <5%
• histologically microvesicular or macrovesicular
• causes
• excessive dietary intake or lipolysis in adipose tissue
• increased endogenous synthesis
• decreased catabolism in liver
• combination
• steatosis itself is not harmful for liver (sometimes is even considered
protective mechanisms), however it represents substrate for increased
lipid peroxidation
• steatohepatitis (SH)
• together with S also necrosis, inflammation and fibrosis
• more serious than simple S (which is reversible when causing factor
ceases)
• it can reverse to normal or progress to fibrosis or cirrhosis
• transition of S to SH enhanced by other factors such as oxidative stress,
endotoxin, immune system, nutrition etc.
• etiology S a SH
• alcoholic
• energetic content of alcohol
• alteration of intermediary metabolism
• inhibition of β-oxidation
• ↑ NADH and acetyl-CoA (↑ synthesis FFA)
• non-alcoholic fatty liver disease (NAFLD) and steatohepatitis
(NASH)
• component of insulin resistance syndrome
• ↑ lipolysis in adipose tissue – ↑ uptake of FFA by liver
• ↑ peroxidation of lipids and ox. stress for hepatocytes
• hypeinsulinemia stimulates synthesis of FFA and TAG
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NAFLD and NASH
• prevalence ∼20 - 30% in industrialised
countries (associated with OBESITY!!!)
• can be difficult to dissect non-alcoholic from
alcoholic damage in countries where alcohol
consumption is socially accepted and common
• definition of non-alcoholic etiology: daily intake
<10g/day in men (i.e. ~140g ethanol per week)
and (~70g ethanol in women)
• pathogenesis of NAFLD/NASH = metabolic
alterations resulting in hepatic triglyceride
accumulation in insulin-resistant states
• insulin resistance is manifested by hyperinsulinemia,
increased hepatic glucose production, and
decreased glucose disposal
• in adipocytes, hyperinsulinemia increases
hormone-sensitive lipase (HSL) activity, resulting in elevated rates of triglyceride lipolysis and
enhanced FFA flux to the liver
• FFAs can either be oxidized in the mitochondria to form ATP or esterified to produce triglycerides for storage or
incorporation into VLDL particles
• in liver, hyperinsulinemia induces SREBP-1c and ChREBP expression, leading to the transcriptional
activation of all lipogenic genes and the enzymatic machinery necessary for the conversion of excess
glucose to fatty acids
• a consequence of increased fatty acid synthesis is increased production of malonyl-CoA, which inhibits
CPT-1, the protein responsible for fatty acid transport into the mitochondria
• thus, in the setting of insulin resistance, FFAs entering the liver from the periphery, as well as those
derived from de novo lipogenesis, will be preferentially esterified to triglycerides.
• ACL, ATP citrate lyase; CPT-1, carnitine palmitoyl transferase-1; FAS, fatty acid synthase; LCE, long-chain
fatty acyl elongase
• NAFLD represent good terrain for lipid peroxidation due to oxidative stress
• ↑ox. stress in ins. resistance (↑ resistin, TNFa, IL-6 and other pro-inflammatory adipokines)
• products of lipid peroxidation – malondialdehyd (MDA) or 4-hydroxynonenal (HNE) –
stimulate Kuppfer and HSC to fibroproduction and chemotaxis of neutrophils
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More advanced (reversible?) liver damage
• result of chronic damage of
hepatocytes
• infection, alcohol, toxic substances,
accumulation of metals (Cu, Fe),
drugs, …
• collagen in normal liver
• I and III in periportal areas
• IV in Disse space
• fibrosis (F) = increased content
of connective tissue
• damaged hepatocyte activate
Kuppfer cells which release paracrine
factors (PDGF and TGF-β)
• activation of hepatic stellate cells
(HSC)
• regulation of blood flow through
sinusoids (↑ resistance)
• synthesis of connective tissue (collagen,
laminin, …)
• release of photolytic enzymes (matrix-
metaloproteinases)
• alteration of morphology of sinusoids
(loss of fenestrations of endothelia),
accumulation of extracel. matrix
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Activation of HSC in fibrosis
/cirrhosis
• HCS activated by
growth factors
from damaged
hepatocytes and
Kuppfer cells
• synthesis of
collagen I and
III in Disse
space
• loss of microvilli
of hepatocytes
• loss of
fenestration of
sinusoids (=
capilarisation of
sinusoids)
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Role of HSC in l. fibrosis on hepatic sinusoidal cells
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Advanced (ireversible) liver damage
• cirrhosis (C)
• histologically micronodular or macronodular
• irreversible change of architecture (lobules,
vessels, collagen)
• parallel processes:
• fibrosis + necrosis + nodular regeneration
• loss of functional parenchyma
• portal hypertension and liver failure
• ↑ risk of carcinoma
• general symptoms of advanced liver
diseases
• weakness, weight loss
• jaundice
• bleeding
• due to deficit of clotting factors
• edema, ascites
• due to hypoalbumiemia
• prolonged action of hormones
• gynecomastia in men
• spider nevi
• liver encephalopathy
• due to hyperamonemonia
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Alcohol and liver - endotoxin
• alcohol increases permeability for endotoxin from intestine to
circulation
• endotoxin is a part of the G-negative bacteria wall
• endotoxin (via receptors CD14 and TLR4) activates Kuppfer cells
(specialized macrophages along liver sinusoids) to production of
cytokines (NFkB) and superoxide (NADPH oxidase)
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Pathophysiological differences between
normal (A) and fibrotic/cirrhotic (B) liver
• In normal liver (A), normal fenestrae along the hepatic sinusoids allow
free passage of blood (arrows) into the Space of Disse, in which, stellate
cells (green) are found. In liver cirrhosis (B), there is an increase in the
number of stellate cells, associated with deposition of collagenous fibers
in the Space of Disse, and loss of fenestrae as the sinusoids become
more capillary-like. As a result, transfer of low-molecular-weight
compounds (e.g. contrast medium) from the sinusoids into the Space of
Disse becomes more impeded (small arrows).
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Consequences of liver cirrhosis
• portal hypertension
• hypoalbumiemia
• disorder of hemostasis
• vitamin K deficit and thus inadequate
formation of clotting factors
• suppression of bone marrow
• due to bleeding, hypersplenism and low K
vitamin resorption
• hyperbilirubinemia or icterus
• decreased degradation of circulating
hormones
• aldosterone
• loss of K by urine, intracel. acidosis,
metabolic alkalosis
• decreased ionization of NH3!!!!
• androgens – increased conversion to estrogens
in periphery
• gynecomasty in men
• pavloučkové névy
• metabolic consequences
• abnormal metabolism of AA (↑ conc. of
aromatic AA – atyp. neurotransmitters in CNS)
• disorder of glucoregulation
• impaired urea cycle
• intrahepatic cholestasis
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Hyperbilirubinemia/icterus
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Portal hypertension
• normal pressure in portal circulation 5 – 15 mmHg
• localization of portal hypertension
• pre-hepatic
• thrombosis v. portae, malformation, compression
• intra-hepatic
• due to cirrhosis, parasites
• post-hepatic
• right heart failure (hepatosplenomegaly), thrombosis of liver veins (Budd-Chiari
syndrome), compression by tumour
• increased pressure before liver sinusoids does not create pressure
overload for liver, after sinusoids it does, therefore damage is greater
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Portal hypertension
• 1) congestion of blood in the v. portae
and stasis of blood in splanchnic organs
• stomach and intestine
• malnutrition and maldigestion
• erosion and ulcers
• increased permeability for bacteria
• spleen
• hypersplenism → destruction of Ery and
platelets
• 2) blood flow through portocaval
anastomoses directly to systemic
circulation
• normally there are small veins
• under the high pressure risk of mechanical
damage and bleeding
• vv. oesophageae (esoph. varices)
• vv. rectales (hemoroids)
• vv. paraumbilicales (caput Medusae)
• 3) ascites and edemas
• fluid in peritoneal cavity due to portal
hypertension + hypoalbumiemia +
retention of Na (aldosterone)
• increased permeability for bacteria =
spontaneous bact. peritonitis
• 5) hepatorenal syndrome
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Esophageal varices
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Liver encephalopathy
• abnormalities of conscience (quantitative and
qualitative), behavior and neuromuscular
functions
• reversible only in initial stages
• impaired detoxification of ammonia in urea
cycle
• sources of ammoniac
• oxidative de-amination by glutamatdehydrogenase
from Glu
• glutaminase from Gln to Glu
• degradation of purines and pyrimidines
• de-amination by monoaminooxidase
• synthesis of hem
• bacteria in large intestine
• ammoniac >50µmol/l toxic for CNS
• in blood as NH3/NH4+
• balance depends on pH (normally 99% ionised)
• alcalosis increases free ammoniac and thus toxicity
• urea (= ornithin) cycle in liver dally produces 20 –
40 g urea
• CO2 + NH4+ →CO(NH2)2 + H2O + 2H+
• 5 enzymes – mitochondria and cytosol
• urea excreted by kidney
• blood from splanchnic contains not only
nutrients by also toxins (ammoniac,
mercaptans, phenols etc. produced by bacteria)
• if not properly detoxified in liver
• formation of “false” neurotransmitters in brain
• change of behavior and conscience, “flapping” tremor,
apraxia
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Intestine and liver - ammonia
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Impaired balance of excitatory
and inhibitory AA in the brain
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Hepatorenal syndrome
• kidney failure
accompanying liver
disease without preexisting
kidney
pathology
• etiology
• Na and water
retention
• hyper-
aldosteronemia
• however, effective
circulating volume is
decreased due to
escape to the third
space (ascites)
• hypoalbuminemia
• decrease of renal
perfusion and GFR
• systemic
vasodilation but
intrarenal
vasoconstriction
• contraction
of afferent
arterioles
(RAS)
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Liver tumors
• benign
• hemangioma
• hematoma
• malign
• hepatocellular
carcinoma
• in 70% consequence of
cirrhosis
• prevalence increases
• poor prognosis
• metastases
• colorectal carcinoma,
…
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Pathophysiology of biliary tract
• cholecystolithiasis (gallstones)
• typically 55-65 yrs ~10% men and ~20%
women
• causes – alteration of the ration between
bile components
• type of stones
• cholesterol (70-90%)
• pigmented (calcium + bilirubin)
• mixed
• increased concentration of cholesterol
• diet, obesity
• decrease of bile acids and phospholipids
• malnutrition, Crohn disease, resection of ileum
• cholecystitis
• stagnation of bile
• diet, starvation
• complications of cholecystholithiasis
• biliary colic (blockade of d. cysticus)
• extrahetal cholestasis (blockade of d.
choledochus)
• inflammation (cholecystitis, cholangoitis)
• acute pancreatitis
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