The underlying basis of immune hydrops is the immunization of the mother by blood group antigens on fetal red cells and the free passage of antibodies from the mother through the placenta to the fetus .
Fetal red cells may reach the maternal circulation during the last trimester of pregnancy, when the cytotrophoblast is no longer present as a barrier, or during childbirth itself. The mother thus becomes sensitized to the foreign antigen.
Of the numerous antigens included in the Rh system, only the .... antigen is a major cause of Rh incompatibility
Which factors influence the immune response to Rh-positive fetal red cells that reach the maternal circulation?
Concurrent ABO incompatibility protects the mother against Rh immunization, because the fetal red cells are promptly coated and removed from the maternal circulation by anti-A or anti-B IgM antibodies that do not cross the placenta.
The antibody response depends on the dose of immunizing antigen; hence, hemolytic disease develops only when the mother has experienced a significant transplacental bleed (more than 1 mL of Rh-positive fetal red cells).
The initial exposure to Rh antigen evokes the formation of IgM antibodies, so Rh disease is uncommon with the first pregnancy. Exposure during a subsequent pregnancy generally leads to a brisk IgG antibody response and the risk of immune hydrop
What is the incidence of ABO incompatibility in pregnancies?
Why is the incidence of HDN low in the setting of ABO incompatibility?
First, as mentioned, most anti-A and anti-B antibodies are of the IgM type and hence do not cross the placenta.
Second, neonatal red cells express blood group antigens A and B poorly.
Third, many cells other than red cells express A and B antigens and thus absorb some of the transferred antibody. ABO hemolytic disease occurs almost exclusively in infants of group A or B who are born of group O mothers.
For reasons unknown, certain group O women possess IgG antibodies directed against group A or B antigens (or both) even without prior sensitization. Therefore, the firstborn may be affected. Fortunately, even with transplacentally acquired antibodies, lysis of the infant's red cells is minimal. There is no effective protection against ABO reactions
What are two consequences of excessive destruction of red cells in the neonate ?
Anemia is a direct result of red cell loss. If hemolysis is mild, extramedullary hematopoeisis in the spleen and liver may suffice to maintain normal levels of red cells.
However, with more severe hemolysis, progressive anemia develops, and may result in hypoxic injury to the heart and liver.
Because of liver injury, plasma protein synthesis decreases, and levels of these proteins may drop to as low as 2 to 2.5 mg/dL.
Cardiac hypoxia may lead to cardiac decompensation and failure.
The combination of reduced plasma oncotic pressure and increased hydrostatic pressure in the circulation (secondary to cardiac failure) results in generalized edema and anasarca, culminating in hydrops fetalis
develops because hemolysis produces unconjugated bilirubin. Bilirubin also passes through the infant's poorly developed blood-brain barrier. Being water insoluble, it blinds to lipids in the brain, resulting in demage to the central nervous system, termed kernicterus
The three major causes of nonimmune hydrops include
cardiovascular defects, chromosomal anomalies, and fetal anemia
What are the cardiac defects causing hydrops?
Both structural and functional cardiovascular defects, such as congenital cardiac defects and arrhythmias, may result in intrauterine cardiac failure and hydrops
What are the chromosomal causes of hydrops?
45,X karyotype (Turner syndrome) and the trisomies 21 and 18
What is the cause of hydrops in chromosomal abnormality?
What are the major nonimmune anemic causes of hydrops?
Homozygous alpha thalasemia
What are the hallmarks of PB19 infection?
The virus gains preferential entry into erythroid precursors (normoblasts), where it replicates, leading to apoptosis of red cell progenitors and isolated red cell aplasia.
Parvoviral intranuclear inclusions can be seen within circulating and marrow erythroid precursors
What is the relation of twin pregnancy to hydrops?
Approximately 10% of cases of nonimmune hydrops are related to monozygous twin pregnancies and twin-to-twin transfusion occurring through anastomoses between the two circulations
The presence of dysmorphic feature in a fetus with hydrops suggest...................
What is the spectrum of gross morphology of hydrops?
hydropsfetalis represents the most severe and generalized manifestation,
lesser degrees of edema such as isolated pleural, peritoneal, or postnuchal fluid collections can occur
What are the morphological characteristics of hydrops fetalis?
In hydrops associated with fetal anemia, both fetus and placenta are characteristically pale;
in most cases the liver and spleen are enlarged from cardiac failure and congestion.
Additionally, the bone marrow demonstrates compensatory hyperplasia of erythroid precursors (parvovirus-associated red cell aplasia being a notable exception), and extramedullary hematopoiesis is present in the liver, spleen, and lymph nodes, and possibly other tissues such as the kidneys, lungs, and even the heart.
The increased hematopoietic activity accounts for the presence in the peripheral circulation of large numbers of immature red cells, including reticulocytes, normoblasts, and erythroblasts (erythroblastosis fetalis)
The affected brain is enlarged and edematous and, when sectioned, has a bright yellow color, particularly the basal ganglia, thalamus, cerebellum, cerebral gray matter, and spinal cord.
Numerous islands of extramedullary hematopoiesis (small blue cells) are scattered among mature hepatocytes in this infant with nonimmune hydrops fetalis.
What are clinical features of hydrops?
Minimally affected infants display pallor, possibly accompanied by hepatosplenomegaly (to which may be added jaundice with more severe hemolytic reactions), whereas the most gravely ill neonates present with intense jaundice, generalized edema, and signs of neurologic involvement.
EYES: Cataract, Cherry red macula, Dislocated lens, Glaucoma
MUSCLE, JOINTS: Myopathy, Abnormal mobility
What are the general features of PKU?
bi-allelic mutations of phenylalanine hydroxylase
The degree of hyperphenylalaninemia and clinical phenotype is inversely related to the amount of residual enzyme activity
What is the spectrum of presentations in PKU?
Infants with mutations resulting in a lack of PAH activity present with the classic features of PKU, while those with up to 6% residual activity present with milder disease.
Moreover, some mutations result in only modest elevations of blood phenylalanine levels without associated neurologic damage (benign hyperphenylalaninemia)
How can we differentiate between benign hyperphenylalaninemia and PKU?
Measurement of serum phenylalanine differentiates benign hyperphenylalaninemia and classic PKU, with the concentrations being typically above 600 μM in PKU (normal phenylalanine concentrations, by contrast, are less than 120 μM).
What is the biochemical abnormality in PKU?
inability to convert phenylalanine into tyrosine
What is the normal phenylalanine hydroxylase system?
In normal children, less than 50% of the dietary intake of phenylalanine is necessary for protein synthesis.
The rest is irreversibly converted to tyrosine by PAH in the liver as part of a complex metabolic pathway, the hepatic PAH system, which, in addition to the enzyme PAH, has two other components: the cofactor tetrahydrobiopterin (BH4) and the enzyme dihydropteridine reductase, which regenerates BH4
What are the causes of hyperphenylalaninemia?
About 98% of cases are attributable to abnormalities in PAH and the remaining 2% to abnormalities in synthesis orrecycling of BH4
What is the importance of BH4?
BH4 is not only an essential cofactor for PAH but is also required for tyrosine and tryptophan hydroxylation.
Concomitant defects in BH4 recycling disturb the synthesis of neurotransmitters.
As a result, in patients with BH4 recycling defects neurologic damage is not arrested despite normalization of phenylalanine levels.
Why it is important to recognize BH4 deficient variant of PKU?
because the ongoing neurologic disturbances cannot be treated by dietary control of phenylalanine levels alone
BH4 is required for........
What are the pathophysiology of symptoms in PKU?
With a block in phenylalanine metabolism due to lack of PAH, minor shunt pathways come into play, yielding phenylpyruvic acid, phenyllactic acid, phenylacetic acid, and o-hydroxyphenylacetic acid, which are excreted in large amounts in the urine in PKU.
Some of these abnormal metabolites are excreted in the sweat, and phenylacetic acid in particular imparts a strong musty or mousy odor to affected infants.
It is believed that excess phenylalanine or its metabolites contribute to the brain damage in PKU.
What is the cause of musty odor in PKU?
true or false: PKU symptoms are present at birth
What is the course of PKU?
Affected infants are normal at birth but within a few weeks develop a rising plasma phenylalanine level, which in some way impairs brain development.
Usually by 6 months of life severe mental retardation becomes evident; fewer than 4% of untreated PKU children have intelligence quotient values greater than 50 or 60.
About one third of these children are never able to walk, and two thirds cannot talk.
Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated children.
What are the features of maternal PKU?
Between 75% and 90% of children born to women with PKU who discontinue diatery treatment are mentally retarded and microcephalic, and 15% have congenital heart disease, even though the infants themselves are heterozygotes.
This syndrome, termed maternal PKU, results from the teratogenic effects of phenylalanine or its metabolites that cross the placenta and affect specific fetal organs during development.
Maternal dietary restriction of phenylalanine should be initiated before conception and continue throughout pregnancy
What is the mc symptom of maternal PKU?
How can BH4 be used for treatment of PKU in some individuals with missense mutation in PAH?
it is believed that this cofactor acts as a “molecular chaperone,” preventing the degradation of misfolded PAH protein.
What are the steps in conversion of galactose to glucose?
Two variants of galactosemia have been identified. In the more common variant there is a total lack of galactose-1-phosphate uridyl transferase (also known as GALT) involved in reaction 2. The rare variant arises from a deficiency of galactokinase, involved in reaction 1
What is the pathophysiology of galactosemia?
As a result of the transferase lack, galactose-1-phosphate accumulates in many locations, including the liver, spleen, lens of the eye, kidneys, heart muscle, cerebral cortex, and erythrocytes.
Alternative metabolic pathways are activated, leading to the production of galactitol (a polyol metabolite of galactose) and galactonate, an oxidized by-product of excess galactose, both of which also accumulate in the tissues.
Long-term toxicity in galactosemics has been variously imputed to these metabolic intermediates.
Heterozygotes may have a mild deficiency but are spared the clinical and pathologic consequences of the homozygous state
What is the morphology of galactosemia?
The liver, eyes, and brain bear the brunt of the damage.
The early-to-develop hepatomegaly is due largely to fatty change, but in time widespread scarring that closely resembles the cirrhosis of alcohol abuse may supervene
Opacification of the lens (cataract) develops, probably because the lens absorbs water and swells as galactitol.
Nonspecific alterations in CNS, including loss of nerve cells, gliosis, and edema, particularly in the dentate nuclei of the cerebellum and the olivary nuclei of the medulla. Similar changes may occur in the cerebral cortex and white matter
What are the major portions of the brain that are involved in galactosemia?
dentate nuclei of the cerebellum and the olivary nuclei of the medulla
Major cause of hepatomegaly in galatosemia is.........
What are the symptoms of galactosemia?
These infants fail to thrive almost from birth.
Vomiting and diarrhea appear within a few days of milk ingestion.
Jaundice and hepatomegaly usually become evident during the first week of life and may seem to be a continuation of the physiologic jaundice of the newborn.
The cataracts develop within a few weeks, and within the first 6 to 12 months of life mental retardation may be detected.
Even in untreated infants, however, the mental deficit is usually not as severe as that seen in PKU.
Accumulation of galactose and galactose-1-phosphate in the kidney impairs amino acid transport, resulting in aminoaciduria.
There is an increased frequency of fulminant Escherichia coli septicemia, possibly arising from depressed neutrophil bactericidal activity.
Hemolysis and coagulopathy in the newborn period can occur as well
How is galactosemia diagnosed?
The diagnosis of galactosemia can be suspected by the demonstration in the urine of a reducing sugar other than glucose, but tests that directly identify the deficiency of the transferase in leukocytes and erythrocytes are more reliable.
Antenatal diagnosis is possible by the assay of GALT activity in cultured amniotic fluid cells or determination of galactitol level in amniotic fluid supernatant
What are the mc mutations in galactosemia?
glutamine-to-arginine substitution at codon 188 (Gln188Arg) is the most prevalent mutation in non-Hispanic whites,
serine-to-leucine substitution at codon 135 (Ser135Leu) is the most common mutation in African Americans
How can most symptoms of galactosemia be prevented?
Many of the clinical and morphologic changes of galactosemia can be prevented or ameliorated by early removal of galactose from the diet for at least the first 2 years of life
Which galactosemia symptoms cannot be prevented by dietary cautions?
older patients are frequently affected by a speech disorder and gonadal failure (especially premature ovarian failure) and, less commonly, by an ataxic condition.
................ is the most common lethal genetic disease that affects Caucasian populations
What is CF by definition?
disorder of ion transport in epithelial cells that affects fluid secretion in exocrine glands and the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts
In many infants this disorder leads to abnormally viscous secretions, which obstruct organ passages, resulting in most of the clinical features of this disorder, such as chronic lung disease secondary to recurrent infections, pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction, and male infertility
Can occur before birth to adolescence
heterozygote carriers for CF have a higher incidence of ............ as compared with the general population
respiratory and pancreatic diseases
The chromosomal abnormality of CFTR is on.....
The primary defect in cystic fibrosis results from ......
abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q
What is the structure of CFTR?
The 1480–amino acid polypeptide encoded by CFTR has two transmembrane domains (each containing six α-helices), two cytoplasmic nucleotide-binding domains (NBDs), and a regulatory domain (R domain) that contains protein kinase A and C phosphorylation sites.
The two transmembrane domains form a channel through which chloride passes.
Activation of the CFTR channel is mediated by agonist-induced increases in cyclic adenosine monophosphate (cAMP), followed by activation of a protein kinase A that phosphorylates the R domain.
Adenosine triphosphate (ATP) binding and hydrolysis occurs at the NBD and is essential for the opening and closing of the channel pore in response to cAMP-mediated signaling
What are the additional role of CFTR?
1) chloride-conductance channel
2) Also regulate multiple ion channels and cellular processes, primarily through interactions involving its NBD: outwardly rectified chloride channels, inwardly rectified potassium channels (Kir6.1), the epithelial sodium channel (ENaC), gap junction channels, and cellular processes involved in ATP transport and mucus secretion.
3) The interaction of CFTR with the ENaC has possibly the most pathophysiologic relevance in cystic fibrosis.
4) The ENaC is situated on the apical surface of exocrine epithelial cells and is responsible for sodium uptake from the luminal fluid, rendering it (the luminal fluid) hypotonic. The ENaC is inhibited by normally functioning CFTR; hence, in cystic fibrosis, ENaC activity increases, markedly augmenting sodium uptake across the apical membrane.
5) The one exception to this rule happens to be the human sweat ducts, where ENaC activity decreases as a result of CFTR mutations; therefore, a hypertonic luminal fluid containing both high sweat chloride (the sine qua non of classic cystic fibrosis) and high sodium content is formed. This is the basis for the “salty” sweat that mothers can often detect in their affected infants
The major function of CFTR in the sweat gland ducts is to ........................................................................
reabsorb luminal chloride ions and augment sodium reabsorption via the ENaC
True or false: The functions of CFTR are tissue-specific
In the sweat ducts, loss of CFTR function leads to ................................................................................................................
Decreased reabsorption of sodium chloride and production of hypertonic sweat
What is the pathophysiology of CF in lung and GI?
in the respiratory and intestinal epithelium, the CFTR is one of the most important avenues for active luminal secretion of chloride.
At these sites, CFTR mutations result in loss or reduction of chloride secretion into the lumen. Active luminal sodium absorption is also increased (due to loss of inhibition of ENaC activity), and both of these ion changes increase passive water reabsorption from the lumen, lowering the water content of the surface fluid layer coating mucosal cells.
Thus, unlike the sweat ducts, there is no difference in the salt concentration of the surface fluid layer coating the respiratory and intestinal mucosal cells in normal individuals versus those with cystic fibrosis.
Instead, the pathogenesis of respiratory and intestinal complications in cystic fibrosis seems to stem from an isotonic but low-volume surface fluid layer.
In the lungs, this dehydration leads to defective mucociliary action and the accumulation of hyperconcentrated, viscid secretions that obstruct the air passages and predispose to recurrent pulmonary infections
CFTR loss leads to........tonic sweat and ....tonic GI fluid
How is CFTR responsible for bicarbonate transport?
The bicarbonate transport function of CFTR is mediated by reciprocal interactions with a family of anion exchangers called SLC26, which are co-expressed on the apical surface with CFTR.
It has been demonstrated in some CFTR mutant variants that chloride transport is completely or substantially preserved, while bicarbonate transport is markedly abnormal.
Alkaline fluids are secreted by normal tissues, while acidic fluids (due to absence of bicarbonate ions) are secreted by epithelia harboring these mutant CFTR alleles.
The decreased luminal pH can lead to a variety of adverse effects such as increased mucin precipitation and plugging of ducts, and increased binding of bacteria to plugged mucins.
Pancreatic insufficiency, a feature of classic cystic fibrosis, is virtually always present when there are CFTR mutations with abnormal bicarbonate conductance
................................... is virtually always present when there are CFTR mutations with abnormal bicarbonate conductance
What is the mc genetic abnormality in CFTR patients?
Class II: Abnormal protein folding, processing, and trafficking.
These mutations result in defective processing of the protein from the endoplasmic reticulum to the Golgi apparatus; the protein does not become fully folded and glycosylated and is instead degraded before it reaches the cell surface.
The most common class II mutation is a deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508). Worldwide, this mutation can be found in approximately 70% of cystic fibrosis patients.
Class II mutations are also associated with complete lack of CFTR protein at the apical surface of epithelial cells
Class I: Defective protein synthesis are associated with..............
complete lack of CFTR protein at the apical surface of epithelial cells
What is meant by Class III: Defective regulation in CF?
Mutations in this class prevent activation of CFTR by preventing ATP binding and hydrolysis, an essential prerequisite for ion transport.
Thus, there is a normal amount of CFTR on the apical surface, but it is nonfunctional
What is the mcc of CF?
Abnormal protein folding, processing, and trafficking: deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508)
What are the features of CF with Decreased conductance?
Occur in the transmembrane domain of CFTR, which forms the ionic pore for chloride transport.
There is a normal amount of CFTR at the apical membrane, but with reduced function.
Class V: Reduced abundance in CF are associated with......
mutation in intronic splice sites or the CFTR promoter
Also milder phenotype
What are the features of class VI mutation in CF?
Altered regulation of separate ion channels.
Mutations in this class affect the regulatory role of CFTR.
In some cases, a given mutation affects the conductance by CFTR as well as regulation of other ion channels. For example, the ΔF508 mutation is both a class II and class VI mutation
Which types of CFTR mutation are associated with milder phenotype?
Class IV: Decreased conductance
Class V: Reduced abundance
What are the six types of CFTR mutation?
Class I: Defective protein synthesis-->complete lack of CFTR protein at the apical surface
Class II: Abnormal protein folding, processing, and trafficking--> MC/complete lack of CFTR protein at the apical surface
Class III: Defective regulation--> abnormal ATP binding and hydrolysis/normal amount but nonfunctional
Class IV: Decreased conductance--> transmembrane domain/ normal amount of CFTR at the apical membrane, but with reduced function/milder phenotype
Class V: Reduced abundance-->intronic splice sites or the CFTR promoter/milder phenotype
Class VI: Altered regulation of separate ion channels
What is the finding in the mildest form of CF?
What is the spectrum of disease in CF?
Thus, two “severe” (class I, II, and III) mutations that produce virtual absence of membrane CFTR are associated with the classic cystic fibrosis phenotype (pancreatic insufficiency, sinopulmonary infections, and gastrointestinal symptoms), while the presence of a “mild” (class IV or V) mutation on one or both alleles results in a less severe phenotype
In CF genotype-phenotype correlation is most consistent for ...................
pancreatic disease, wherein the presence of a “mild” mutation in one allele can revert to the pancreatic insufficiency phenotype conferred by homozygosity for “severe” mutations
In CF genotype-phenotype correlations are far less consistent in .....................
pulmonary disease, reflecting an effect of secondary modifiers
What are some features of atypical CF?
idiopathic chronic pancreatitis
late-onset chronic pulmonary disease
obstructive azoospermia caused by bilateral absence of the vas deferens
What are some genetic modifiers of CF?
The severity of pulmonary manifestations in CF is associated with polymorphic variants at mannose-binding lectin 2 (MBL2) and transforming growth factor β1 (TGFB1).
MBL is a key effector of innate immunity involved in opsonization and phagocytosis of microorganisms, and polymorphisms in the MBL2 gene that are associated with lower circulating levels of the protein confer a threefold higher risk of end-stage lung disease.
TGFβ is a direct inhibitor of CFTR function. Polymorphisms in the 5′ end of the TGFB1 gene to be associated with severe pulmonary phenotypes.
What is the environmental modifier in CF?
1) Defective mucociliary action because of deficient hydration of the mucus results in an inability to clear bacteria from the airways.
2) Pseudomonas aeruginosa species, in particular, colonize the lower respiratory tract, first intermittently and then chronically.
3) Concurrent viral infections predispose to such colonization. The static mucus creates a hypoxic microenvironment in the airway surface fluid, which in turn favors the production of alginate, a mucoid polysaccharide capsule.
4) Alginate production permits the formation of a biofilm that protects the bacteria from antibodies and antibiotics, allowing them to evade host defenses, and produce a chronic destructive lung disease.
5) Antibody- and cell-mediated immune reactions induced by the organisms result in further pulmonary destruction, but are ineffective against the organism.
What is the morphology of sweat gland in CF?
sweat glands are morphologically Unaffected in all forms
What are the spectrum of pancreatic abnormlaities in CF?
Pancreatic abnormalities are present in approximately 85% to 90% of patients with cystic fibrosis.
In the milder cases, there may be only accumulations of mucus in the small ducts with some dilation of the exocrine glands.
In more severe cases, usually seen in older children or adolescents, the ducts are completely plugged, causing atrophy of the exocrine glands and progressive fibrosis.
Atrophy of the exocrine portion of the pancreas may occur, leaving only the islets within a fibrofatty stroma.
The loss of pancreatic exocrine secretion impairs fat absorption, and the associated avitaminosis A may contribute to squamous metaplasia of the lining epithelium of the ducts in the pancreas, which are already injured by the inspissated mucus secretions.
Thick viscid plugs of mucus may also be found in the small intestine of infants. Sometimes these cause small-bowel obstruction, known as meconium ileus
The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue.
What are the mildest changes in pancreas in CF?
accumulations of mucus in the small ducts with some dilation of the exocrine glands
What is the liver involvement morphology in CF?
Bile canaliculi are plugged by mucinous material, accompanied by ductular proliferation and portal inflammation.
Over time, focal biliary cirrhosis develops in approximately a third of patients, which can eventually involve the entire liver, resulting in diffuse hepatic nodularity.
What are the changes in salivary gland in CF?
progressive dilation of ducts, squamous metaplasia of the lining epithelium, and glandular atrophy followed by fibrosis.
.......................................................................................................... are the three most common organisms responsible for lung infections in CF
Staphylococcus aureus, Hemophilus influenzae, and Pseudomonas aeruginosa
What are the lung infections in CF?
Staphylococcus aureus (MC in younger than 20), Hemophilus influenzae, and Pseudomonas aeruginosa (mc in older than 20) are the three most common organisms responsible for lung infections
B. cenocepacia, Stenotrophomonas maltophila and nontuberculous mycobacteria, ABPA
What are the pulmonary histopathological changes in CF?
These stem from the viscous mucus secretions of the submucosal glands of the respiratory tree leading to secondary obstruction and infection of the air passages.
The bronchioles are often distended with thick mucus associated with marked hyperplasia and hypertrophy of the mucus-secreting cells.
Superimposed infections give rise to severe chronic bronchitis and bronchiectasis or abscess
What are the fertility findings in men with CF?
Azoospermia and infertility are found in 95% of the males
congenital bilateral absence of the vas deferens
What are the lung manifestations of CF?
a.Persistent colonization/infection with typical cystic fibrosis pathogens, including Staphylococcus aureus, nontypeable Haemopilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Burkholderia cepacia
b. Chronic cough and sputum production
c. Persistent chest radiograph abnormalities (e.g., brochiectasis, atelectasis, infiltrates, hyperinflation)
d. Airway obstruction manifested by wheezing and air trapping
e. Nasal polyps; radiographic or computed tomographic abnormalities of paranasal sinuses
b. Pancreatic: pancreatic insufficiency, recurrent acute pancreatitis, chronic pancreatitis
c. Hepatic: chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis, or multilobular cirrhosis, prolonged neonatal jaundice
d. Nutritional: failure to thrive (protein–calorie malnutrition), hypoproteinemia, edema, complications secondary to fat-soluble vitamin deficiency
What are other manifestations of CF?
Salt-loss syndromes: acute salt depletion, chronic metabolic alkalosis
Male urogenital abnormalities resulting in obstructive azoospermia (congenital bilateral absence of vas deferens)
What are the criteria for diagnosing CF?
One or more characteristic phenotypic features, OR a history of cystic fibrosis in a sibling, OR a positive newborn screening test result
AND An increased sweat chloride concentration on two or more occasions OR identification of two cystic fibrosis mutations, OR demonstration of abnormal epithelial nasal ion transport
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with cystic fibrosis and is associated with ..............................................
“severe” CFTR mutations on both alleles (e.g., ΔF508/ΔF508)
10% to 15% of patients with ....................................................................... retain enough pancreatic exocrine function so as not to require enzyme supplementation
one “severe” and one “mild” CFTR mutation (ΔF508/R117H) or two “mild” CFTR mutations
What are the pancreatic complications in CF?
Manifestations of malabsorption (e.g., large, foul-smelling stools, abdominal distention, and poor weight gain) appear during the first year of life.
The faulty fat absorption may induce deficiency of the fat-soluble vitamins, resulting in manifestations of avitaminosis A, D, or K. Hypoproteinemia may be severe enough to cause generalized edema.
Persistent diarrhea may result in rectal prolapse in up to 10% of children with cystic fibrosis.
The pancreas-sufficient phenotype is usually not associated with other gastrointestinal complications, and in general, these individuals demonstrate excellent growth and development.
“Idiopathic” chronic pancreatitis occurs in a subset of patients with pancreas-sufficient cystic fibrosis and is associated with recurrent abdominal pain with life-threatening complications. These patients have other features of cystic fibrosis, such as pulmonary disease
By contrast, “idiopathic” chronic pancreatitis can also occur as an isolated late-onset finding in the absence of other stigmata of cystic fibrosis; bi-allelic CFTR mutations (usually one “mild,” one “severe”) are demonstrable in the majority of these individuals who have nonclassic or atypical cystic fibrosis.
Endocrine pancreatic insufficiency (i.e., diabetes) is uncommon in cystic fibrosis and is usually accompanied by substantial destruction of pancreatic parenchyma
What is the mcc of death in CF?
Cardiorespiratory complications, such as persistent lung infections, obstructive pulmonary disease, and cor pulmonale
Patients with mild pulmonary disease in CF usually have ................pancreatic disease
little or no
Children who present with ...................... must be tested for CF
Recurrent sinonasal polyps
symptomatic or biochemical liver disease in CF has its onset .....................
at or around puberty
What is the change in nasal transepithelial potential in CF?
individuals with cystic fibrosis demonstrate a significantly more negative baseline nasal potential difference than controls