Disorders OF PROTEIN METABOLISM

DISORDERS OF PROTEIN METABOLISM

1. DISORDERS OF PROTEIN METABOLISM PRESENTED BY BAZILA ILLAHI BDS 3 RD YEAR ROLL NO : 15

2. CONTENTS : BRIEF OVERVIEW OF PROTEINS DEFINITION OF PROTEINS TYPES OF PROTEINS BIOLOGICAL FUNCTIONS ROLE IN DENTISTRY PROTEIN METABOLISM OVERVIEW METABOLIC DISTURBANCES OF PROTEINS

3. PROTEIN ENERGY MALNUTRITION AMYLOIDOSIS GOUT PRION DISEASE INBORN ERRORS OF METABOLISM

4. DEFINITION OF PROTEINS Proteins are defined as complex biological compounds of higher molecular weight containing nitrogen,hydrogen,oxygen,carbon and small amounts of sulphur. Another definition proposed by Mulder : High molecular nitrogen rich and most abundant substances present in plants and animals.

5. STRUCTURE OF A PROTEIN

6. Sources of proteins Meat Fish Cheese Beans Yogurt Nuts Lentils Seeds Eggs

7. Daily requirements One gram of protein is required for each kg of body weight. However requirement can increase in various normal physiological situations like: Last half of pregnancy During lactation Infancy Childhood Adolescence

8. Types of proteins On the basis of composition : Simple proteins :- contain only a.a Conjugate proteins :- contain a non a.a component in addition to the a.a Complete proteins :- contain sufficient amount of essential a.a Incomplete proteins :- contain insufficient quantities of one or more essential a.a Complementary proteins :- incomplete when ingested singly,but when combined provide sufficient essential a.a

9. Types of proteins (CoNTD.) On the basis of function : Hormonal Enzymatic Structural Defensive Storage Transport Receptor Contractile

10. Biological functions Static functions :- provides stucture and strength to the body e.g collagen. Dynamic functions :- hormonal, enymatic, defensive etc. Source of energy Role in dentistry :- Pre-eruptive and post-eruptive effects on teeth as they form an integral component of cells necessary for the normal development of teeth and specifically for the formation of matrix of hard tissues of teeth e.g Amelogenin,BMP. Chemical nature of protein foods can neutralize the acids produced by oral bacteria. Dental pellicle- an acellular layer of salivary proteins protects the enamel against abrasion and serves as a diffusion barrier thus preventing the solubility of enamel surface.

11. Protein metabolism overview Dietary protein body proteins Protein synthesis amino acids synthesis of N-compounds α -ketoglutarate transamination glutamate deamination ketoacids ammonia urea Energy Glucose Fat Non-essential amino acids

12. Protein metabolism (contd.) Amino acid contains two components: Carbon skeleton - its converted to keto acids a.a transamination Keto acids . Amino group - its converted to urea as an excretory product. a.a deamination Urea

13. Metabolic disturbances of proteins Protein Energy Malnutrition (PEM) :- PEM is a spectrum of diseases whose essential feature is a deficiency of protein at one end as in Kwashiorkor and ; total inanition(starvation of infant due to severe and prolonged restriction of all food at other end as in Marasmus . In the middle of spectrum,there is Marasmic Kwashiorkor in which there are clinical features of both disorders.

14. Causes of PEM :- Dietary deficiency Serious illness Infections in babies Low socio-economic status Problems in mother leading to inadequate production of milk Dietary factors like inadequate breast feeding, ignorance of weaning

15. PROTEIN ENERGY MALNUTRITION KWASHIORKOR MARASMUS CAUSES CLINICAL MANIFESTATIONS INVESTIGATIONS TREATMENT

16. Pem is presented as :- Kwashiorkor Marasmus

17. kwashiorkor Introduction – Its a maladaptive response to starvation due to lack of physiological adaptation to unbalanced deficiency where body utilizes proteins and conserves fat Occurrence – Seen predominantly between 1-5 years of age Causes – Due to insufficient intake of proteins, as the diet of weaning child mainly consists of carbohydrates

18. Biological manifestations – Decreased plasma albumin levels Visceral compartment is severely affected Hypoproteinemia and hypoglycemia Decreased level of electrolytes Low enzyme levels Percentage of body water is increased Iron deficiency anemia Fatty liver (due to decreased synthesis of carrier proteins of lipoproteins) Hypoplastic bone marrow Decreased immunity Multi-vitamin deficiency

19. Clinical symptoms - Weight is about 60-80 % of normal as loss of true weight is masked by increased fluid retention Generalized edema (due to decreased colloidal osmotic pressure) of pitting variety Sparing of subcutaneous fat and muscle mass as body utilizes its proteins to compensate the deficient state Swollen abdomen Moon face Characteristic skin lesions with alternating layers of hyperpigmentation, desquamation hypopigmentation; giving a flaky paint appearance Hair changes like loss of colour or alternate bands of pale and darker colour, straightening and loss of firm attachment to scalp Diarrhoea (due to impaired synthesis of digestive enzymes and loss of electrolytes in stools) Eyelashes give a ‘ Broomstick ’ appearance Dehydration (due to diarrhoea and vomitting) Prone to infections Psychomotor changes (due to cerebral atrophy)

20. Oral manifestations of Kwashiorkor – Bright reddening of tongue with loss of papillae Bilateral angular cheilosis (inflammation) Fissuring of lips Loss of circumoral pigmentation Crowded and rotated teeth giving an appearance of mouth full of jumbled teeth Delayed eruption and hypoplasia of deciduous teeth Mouths of Kwashiorkor patients have been described by Van Wyk to be dry, dirty, caries free, easily traumatized with epithelium readily become detached from the underlying tissue, leaving a raw, beeding surface Incisor and molar growth is retarded Radicular osteocementum decreased Increased acid solubility of enamel of incisors Decreased salivary volume

21. Oral cytological smear study – Perinuclear vacuolization or halo around nucleus in a remarkable number of epithelial cells which is interpreted as a sign of atrophy Investigations – Routine tests :- Full blood count - Stool and urine study – KETONURIA Blood glucose profile - HYPOGLYCEMIA Hb estimation - ANEMIA B . Non-routine tests :- Hair analysis – ALTERNATE BANDS OF HAIR Skin biopsy - PARAKERATOSIS WITH DESQUAMATION Oral findings – bleeding surface

22. Treatment – Provide adequate nutrition by dietary supplements Restore normal body composition Dietary support in the form of 3-4 gm protein and 200 cal/kg body weight Cure the conditions that cause the deficiency Prevention – Breastfeeding a baby for at least 6 months to prevent PEM Improved food distribution systems, public health programs and agricultural development should be promoted

23. marasmus Introduction – Its an adaptive response to starvation Occurrence – Seen mostly in the first year of life Causes – Due to deficiency of calories Biological manifestations – Serum albumin level normal or slightly decreased Somatic compartment of proteins is lost Anemia Multi vitamin deficiency Immune deficiency Hypoplastic bone marrow with increased red cell precursors

24. Clinical symptoms – Growth retardation due to low calorie intake Loss of muscle mass as muscle proteins are mobilised as use for fuel to provide body with a.a as a source of energy to compensate malnutrition. Due to muscle wasting rib cage is prominent Subcutaneous fat is lost due to lipolysis Lean body, so head appears too large Body weight falls to 60 % of normal Child looks older than his age Weakened body is under stress More chances of infections Dry and baggy skin Sparse hair and wrinkled appearance (Old man face) No edema Bones are prominent due to absence of fat around them Hypotension and slow pulse

25. Investigations – Full blood count - Electrolyte, serum protein level study – ALBUMIN LEVEL NORMAL OR LOW. Blood glucose level - Treatment – Dietary support by giving food as proteins and supplements Bring the child out of starvation

26. Points of differentiation between kwashiorkor and marasmus kwashiorkor marasmus Malnutrition that occurs due to insufficient intake of proteins Large belly, diarrhoea, pigmented skin, hair changes Children of 1-5 yrs age Weaned from mother’s milk to a diet low in protein Edema-Present (pitting type) 60-80 % of normal body wt. Decreased plasma albumin Treated by High protein foods Malnutrition that occurs due to starvation (i.e deficiency of proteins, carbs. and fats in diet Muscle wasting, skin foldings, prominent rib cage , shrunken abdomen Children under 1 yr Failed breastfeeding (inadequate calorie intake) Absent, rather wasting Less than 60 % of normal Normal / slightly decreased plasma albumin Treated by a Well banced diet

27. kwashiorkor marasmus

28. AMYLOIDOSIS INTRODUCTION PATHOGENESIS CLASSIFICATION CLINICAL MANIFESTATIONS ORAL MANIFESTATIONS DIAGNOSIS BIOPSY EXAMINATION VARIOUS TESTS TREATMENT

29. AMYLoiDOSIS Introduction :- Disorder characterized by extracellular deposits of fibrillar proteins which is a result of aggregation of misfolded proteins. Misfolded proteins being unstable start self associating forming oligomers and fibrils that r deposited in tissues.

30. Pathogenesis :-

31. FORMS OF AMYLOID PROTEINS :- Amyloid light chain protein (AL )- Here IG light chains accumulate due to monoclonal B cell proliferation affecting heart Amyloid associated protein ( AA )- Here SAA accumulates due to increased activation by chronic inflammatory mediators affecting liver mainly. A B amyloid – Here APP deposits in the cerebral vessels. Transthyretin – Here ATTR accumulates due to mutation of normal transthyretin. B 2 Microglobulin – accumulates in patients with renal disease ,with deposits in joints.

32. Classification :- Systemic amyloidosis – Immunocyte dyscrasias wth Amy. (AL Protein accumulation) Reactive sytsemic Amy . (AA Protein) Heriditary amyloidosis – Familial mediterranean fever (AA Protein) Senile Amy . (ATTR Protein) Familial amyloidotic neuropathies (ATTR Protein) Localized amyloidosis – Senile cerebral ( A B Protein) Senile cardiac (ATTR Protein)

33. Clinical manifestations :- Weakness,fatigue,weightloss Renal and hepatic diseases Proteinuria Cardiac arrythemia Changes in skin color Clay-colored stools Feeling of fullness Joint pain Low red blood cell count (anemia) Shortness of breath Swelling of the tongue Tingling and numbness in legs and feet Weak hand grip

34. Oral manifestations :- Tongue amyloidosis Palatal amyloidosis

35. Tongue amyloidosis :- Feature of systemic amyloidosis Macroglossia with nodular deposits Lateral ridging of enlarged tongue due to teeth indentation Firm tongue with yellow nodules on lateral surface Interference with taste and hyposalivation may result from amyloid deposition in salivary glands Xerostomia n tongue pain Sub mandibular swelling due to tongue enlargement can lead to respiaratory obstruction .

36. Palatal amyloidosis :- Rare condition Feature of localized amyloidosis Nodular deposits found on palate ,nasal septum and maxillary sinus.

37. Diagnosis :- It requires Demonstration of amyloid in tissues Demonstration of plasma cell dyscrasia For demonstration of tissue amyloid :- BIOPSY - Fine needle aspiration of abdomenal fat. Tissues for non-invasive biopsy are gingiva, salivary glands, rectum and skin. Histological feature is Apple Green Birefringence with Congo red dye and viewed under polarised microscope. Other dyes like Thioflavin,Hematoxylin and Eosin are also used.

38. Apple green birefringence seen in histologic section

39. For demonstration of plasma cell dyscrasia :- Bone marrow biopsy showing gamma and kappa light chain producing plasma cells. Presence of monoclonal light chains in serum and urine. Serum Free Light Chain assay (FLC) Imaging techniques for assessment of organ involvement

40. Treatment :- (Aim is to reduce the supply of amyloidogenic monoclonal light chains by suppressing the underlying Plasma cell dyscrasia) High-dose chemotherapy withstem cell transplant can help remove the substance that leads to amyloid formation in those with primary AL amyloidosis. Secondary (AA) amyloidosis is treated with powerful anti-inflammatory medicines called steroids, which fight inflammation. Liver transplant may stop the disease in those with hereditary amyloidosis.

41. A kidney or heart transplant may also be recommended. Diuretic medicine to remove excess water from your body Thickeners to add to fluids to prevent choking in those who have swelling of the tongue Compression stockings to relieve swelling in the legs or feet Diet modifications, especially for those with gastrointestinal amyloidosis

42. GOUT Introduction Pathogenesis Clinical manifestations Oral manifestations Diagnosis treatment

43. gout Introduction – Gout is an inflammatory disease caused by deposition of monosodium urate monohydrate crystals in and around synovial joints. Epidemology – Levels are higher are in men, increase with age and are associated with body weight . Pathophysiology – It can be due to diminished renal excretion ; or increased intake of red meat ; or over production of uric acid .

44. Clinical features – Severe pain Extreme tenderness Marked swelling with overlying red shiny skin Crystals may deposit in joints and soft tissues to produce irregular firm nodules called TOPHI . Investigations – Aspiration of urate crystals from a joint, bursa and tophus Biochemical screen including renal function, uric acid, glucose and lipid profile should be performed Levels of ESR and CRP Radiographs

45. Treatment – Oral NSAIDs for pain relief Local icepacks Oral colchicine Joint aspiration with intra articular steroid injection Oral corticosteroids Urate lowering therapy Allopurinol drug which reduces conversion of hypoxanthine and xanthine to uric acid.

46. PRION DISEASE Prion Disease affecting humans Oral manifestations CLINICAL FEATURES DIAGNOSIS PREVENTION

47. Prions Are the unique proteineceous infectious agents. Devoid of nucleic acid. Transmitted by acquisition of normal mammalian protein (prion protein PrPc) which is in an abnormal conformation(PrPsc ) due to replacement of alpha helices by beta sheets. The abnormal protein inhibits the enzyme proteasome 26S, leading to vicious circle of further accumulation of abnormally configured PrPsc instead of normally configured PrPc .

48. Prions diseases Introduction – Rare disorders which include diff. forms of CREUTZFELDT JAKOB Disease (CJD) as well as animal diseases such as SCRAPIE disease in sheep and Mad cow disease in cattles. Epidemology – Common in middle aged to elderly . Pathology – Due to mutations in gene coding for prion protein .

49. Pathophysiology of prion disease

50. Oral manifestations of prions diseases are extremely rare with features as :- Pseudobulbar palsy may cause dysphagia. Dysarthria and Orofacial dysesthesia . Paresthesia, as well as loss of taste and smell.

51. Clinical features – Progressive dementia Characteristic EEG pattern due to brain atrophy Visual disturbances Diagnosis – By immunohistochemical staining Blood test EEG Cerebrospinal fluid test

52. Prevention – The theoretical risk of transmission of prion disease through dental treatment points to the importance of maintaining optimal standards of infection control and decontamination for infectious agents, including prions.

53. INBORN ERRORS OF AMINO ACID METABOLISM DISORDERS OF PHENYLALANINE N TYROSINE PHENYLKETONURIA TYROSINEMIA ALKAPTONURIA ALBINISM CYSTINURIA CYSTINOSIS HARTNUP DISEASE MAPLE SYRUP DISEASE

54. Inborn errors of metabolism

55. iNborn errors of amino acid metabolism :- Phenylketonuria :- Enzyme defect in Phenylalanine / tyrosine degradation leading to metabolic disorder. Here, the deficiency of hepatic enzyme Phenylalanine Hydroxylase results in accumulation of Phenylalanine. Phenylalanine Tyrosine P.HYDROXYLASE Phenyketonuria

56. Oral manifestations – Prominent cheek and jaw bones Widely spaced teeth Poor development of tooth enamel. Patients are susceptible to tooth wear(erosion)

57. Clinical manifestations – Mental retardation due to its accumulation Hypopigmentation of hair and skin Treatment – Diet low in phenylalanine amino acid Diet with sufficient amount of tyrosine (to compensate for its absence)

58. Alkaptonuria :- Its due to absence of Homogentisate oxidase activity which is necessary for breakdown of Homogenetisic acid. As such Homogentisate accumulates in tissues . Phenylalanine Tyrosine Homogenitisic acid H.OXIDASE Alkaptonuria Intermediates in TCA

59. Clinical features – Dark urine : also known as Black Urine disease Homogenetistic acid urination Alkapton (Black colur) Ochronosis (alkapton deposition in bones, nose, ear,eyes, etc.) Arthritis Treatment – Not a dangerous disorder, so no specific treatment.

60. Albinism :- It is due to lack of synthesis of pigment Melanin which is due to defect in tyrosinase enzyme, the most responsible enzyme for Melanin synthesis. PHENYLALNINE TYROSINE Tyrosinase DOPA ALBINISM

61. Clinical features – Photophobia Susceptibility to Parkinson’s disease (as no DOPA formed) Hypopigmentation in the form of : Vitiligo – loss of pigmentation around mouth, nose, eyes, nipples Leukoderma – loss of pigmentation begins with hands

62. Tryosinemia :- It results due to loss of Tyrosine transaminase which is required for the degradation of Tyrosine. (Type 1) Phenylalanine Tyrosine T.transaminase TYROSINEMIA Breakdown product

63. Clinical features – Hepatic dysfunction, cirrhosis Liver failure Hyperkeratosis Treatment – Diets low in in Tyrosine, Phenylalanine are recommended.

64. Cystinuria :- Characterized by increased excretion of Cystine due to defective carrier system which is normally present for re-absorption of amino acids leading to excretion of amino acids in urine . Cystine Reabsorption carrier system in kidney Cystinuria

65. Clinical features – Cystine stones in kidneys (due to its insolubility) Treatment – Aim of treatment is to increase its solubility and thus reduce stone formation in kidneys.

66. Homocystinuria :- Due to accumulation of homocystine Features – Thrombosis, Osteoporosis, MI, Stroke, etc

67. Hartnup’s disease :- It’s a hereditary disorder of Tryptophan metabolism characterized by low plasma levels of Tryptophan and their elevated urinary excretion. Clinical manifestations – Rash, light sensitivity Cerebellar ataxia Dermatitis Mental retardation Treatment – Dietary Niacin is given

68. Maple Syrup Urine Disease :- It’s a metabolic disorder of branched chain amno acids. The urine smells like Maple syrup or Burnt sugar, hence the name . Branched chain keto a.a Acetyl CO-A acid dehyrogenase MSUD

69. Symptoms – Lethargy Maple syrup odour of urine Coma Mental retardation Treatment – To feed with a diet having low content of branched chain amino acids

70. Isovaleric acidemia :- Inborn error of leucine metabolism with defect in enzyme Isovaleric Co-A dehyrogenase. Oral manifestation – Cheesy odour in breath Treatment – Limit intake of leucine in diet

71. Cystinosis :- Cystine storage disease where cystine crystals are deposited in many tissues n organs of RES . Cause – Lysosomal dysfunction

72. Glycinuria :- When excessive amount of glycine is excreted in urine due to defective renal reabsorption . Symptoms – Increased tendency for formation of oxalate crystal stones.

73. bibliography Shafer’s Textbook of oral pathology (7 th edition) U.satyanarayan textbook of biochemistry (3 rd edition) Robbin’s book of basic pathology (9 th edition) Davidson’s book of medicine (22 nd edition) Neville’s textbook of oral and maxillofacial pathology (2 nd edition) Neurol Neurosurg Psychiatry 2004;75(Suppl I):i36–i42. doi: 10.1136/jnnp.2004.036137 PEM by Keith P. West, Jr., Dr.P.H.international nutrition Oral Manifestations of Malnutrition III. The Effect of Proteins Pages with reference to book, From  119  To  122  Mohammad Iqbal Khadim   (  Dentistry Department, Khyber Medic College, Peshawar.  )